Novel compounds, their use and preparation

ABSTRACT

The invention provides 2, 3-, 4- or 5-substituted-N1-(arylsulfonyl)indole and (heteroaryl)indole compounds of the general formula (I):  
                 
 
     in which Ar, R 2 , R 3 , R 4  and R 5  are as defined in the specification. The compounds bind to the 5-HT 6  receptor and are useful for the treatment and prophylaxis of disorders mediated by the 5-HT 6  receptor, such as obesity and CNS disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from Swedish Patent ApplicationNo. 0003810-9, filed Oct. 20, 2000, and U.S. Provisional PatentApplication No. 60/243,115, filed Oct. 25, 2000. These applications areincorporated herein by reference in their entirety.

TECHNICAL FIELD

[0002] The present invention relates to novel 2-3-, 4- or5-substituted-N1-(arylsulfonyl)indole compounds and(heteroarylsulfonyl)indole compounds, to pharmaceutical compositionscomprising the compounds and to the use of the compounds for thepreparation of a medicament for the treatment of obesity and CNSdisorders as well as method of treatment of these disorders.

BACKGROUND ART

[0003] Obesity is a condition characterized in an increase in body fatcontent resulting in excess body weight above accepted norms. Obesity isthe most important nutritional disorder in the western world andrepresents a major health problem in all industrialized countries. Thisdisorder leads to increased mortality due to increased incidences ofdiseases such as cardiovascular disease, digestive disease, respiratorydisease, cancer and NIDDM (type II diabetes). Searching for compounds,which reduce body weight has been going on for many decades. One line ofresearch has been activation of serotonergic systems, either by directactivation of serotonin receptor subtypes or by inhibiting serotoninreuptake. The exact receptor subtype profile required is however notknown.

[0004] Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of theperipheral and central nervous system, modulate a wide range ofphysiological and pathological functions, including anxiety, sleepregulation, aggression, feeding and depression. Multiple serotoninreceptor subtypes have been identified and cloned. One of these, the5-HT₆ receptor, was cloned by several groups in 1993 (M Ruat, ETraiffort, J-M Arrang, J Tardivel-Lacombe, J Diaz, R Leurs, J-C Shwartz.Biochem. Biophys. Res. Commun. 1993, 193 (1) 268-276; M Sebben, HAnsanay, J Bockaert, A Dumuis, NeuroReport 5, 2553-2557 (1994).) Thisreceptor is positively coupled to adenylyl cyclase and displays affinityfor antipsychotics such as clozapine. Recently, the effect of 5-HT₆antagonist and 5-HT₆ antisense oligonucleotides to reduce food intake inrats has been reported (J C Bentley, C A Mardsen, A J Sleight and K CFone. Effect of 5-HT₆ antagonist Ro 04-6790 on food consumption in ratstrained to a fixed feeding regime. Br J Pharmacol. 1999 Suppl. 126, P66;J C Bentley, A J Sleight, C A Mardsen, K C F Fone. 5-HT₆ antisenseoligonucleotide ICV affects rat performance in the water maze andfeeding. J Psychopharmacol Suppl A64, 1997, 255).

[0005] Compounds with enhanced affinity and selectivity for the 5-HT₆receptor have been identified, e.g. in WO 00/34242 and by M. Isaac, A.Slassi, T. Xin, N. MacLean, J. Wilson, K. McCallum, H. Wang and L.Demchyshyn: 6-Bicyclopiperazinyl-1-arylsulfonylindoles and6-Bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel, potentand selective 5-HT₆ receptor antagonists; Bioorganic & MedicinalChemistry Letters 2000, 10, 1719-1721.

DETAILED DESCRIPTION OF THE INVENTION

[0006] According to the present invention it has been found that thecompounds of formula (I) show affinity for the 5-HT₆ receptor asantagonists at a low nanomolar range. The 5-HT₆ antagonist compounds ofthe present invention are useful for the treatment or prophylaxis ofobesity and for the treatment or prophylaxis of memory and CNS disorders(schizophrenia, Parkinson's disease and depression), Attention DeficitHyperactive Disorders (ADHD), and drug abuse.

[0007] According to the invention, a compound of the general formula (I)is provided:

[0008] wherein

[0009] Ar is

[0010] (1) phenyl,

[0011] (2) naphthyl,

[0012] (3) a 5- to 10-membered monocyclic or bicyclic heterocyclic ringhaving 1 to 4 heteroatoms selected from the group consisting of oxygen,sulfur, or nitrogen, or

[0013] (4) —R⁹-phenyl;

[0014] wherein the phenyl, naphthyl, or heterocyclic ring is optionallysubstituted with halogen, C₁₋₆ alkyl, CF₃, hydroxyl, C₁₋₆ alkoxyl, OCF₃,COCF₃, CN, NO₂, phenyloxy, phenyl, C₁₋₆ alkylsulfonyl, C₂₋₆ alkenyl,—NR⁷R⁸, C₁₋₆ alkylcarboxyl, formyl, —C₁₋₆ alkyl-NH—CO-phenyl, —C₁₋₆alkyl-CO—NH-phenyl, —NH—CO—C₁₋₆ alkyl, —CO—NR⁷R⁸, or SR⁷; wherein eachof R⁷ and R⁸ is independently H or C₁₋₆ alkyl; and R⁹ is C₁₋₆ alkyl orC₂-₆ alkenyl, either of which is optionally substituted with phenyl orphenyloxy;

[0015] R² is H, phenyl, 1, or C₁₋₆ alkyl;

[0016] R³ is H or 3-(1-azabicyclo[2.2.2]oct-2-en)yl;

[0017] R⁴ is H or is selected from the group consisting of:

[0018] wherein R⁶ is H, C₁₋₆ alkyl, or benzyl; and

[0019] R⁵ is H, hydroxy, C₁₋₃ alkoxy, F, NO₂, CF₃, OCF₃, or is selectedfrom the group consisting of:

[0020] or a pharmaceutically acceptable salt, hydrate, or stereoisomerthereof, with the proviso that when R² is alkyl, R⁴ is not H.

[0021] The term “C₁₋₆ alkyl” denotes a straight or branched alkyl grouphaving from 1 to 6 carbon atoms. Examples of alkyl include methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl andstraight- and branched-chain pentyl and hexyl.

[0022] The term “alkenyl” refers to a straight or branched hydrocarbonchain containing 2 to 6 carbon atoms and one or more (e.g., 1, 2, or 3)double or triple bonds, respectively. Some examples of alkenyl areallyl, 2-butenyl, 2-pentenyl, and 2-hexenyl.

[0023] The term “C₁₋₆ alkoxy” denotes a straight or branched alkoxygroup having from 1 to 6 carbon atoms. Examples of said lower alkoxyinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy, t-butoxy and straight- and branched-chain pentoxy andhexoxy.

[0024] The term “halogen” shall mean fluorine, chlorine, bromine oriodine. The term “heterocyclic ring” refers to a cyclic moiety of theindicated size and having 1-4 heteroatoms (ring atoms) selected from thegroup consisting of nitrogen, oxygen, and sulfur. A heterocyclic ringcan be completely saturated, partially saturated, or unsaturated. Inother words, a heterocyclic ring can be a heterocycloalkyl,heterocycloalkenyl (containing one or more double bonds) or heteroaryland may contain fused rings. Examples of a heterocyclic ring includepiperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl,morpholinyl, pyridyl, furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl,imidazolyl, indolyl, benzofuranyl, and benzthiazolyl. When appropriate,the nitrogen ring atoms of a heterocyclic ring can be —NH—, —N(C₁₋₆alkyl)—, or —N(—CO—CF₃)—.

[0025] In a preferred embodiment, the invention features a compound offormula (I), supra, wherein

[0026] Ar is

[0027] (1) phenyl that is unsubstituted or optionally mono- orpoly-substituted with halogen, C₁₋₆ alkyl, CF₃, hydroxyl, C₁₋₆ alkoxyl,OCF₃, CN, NO₂, phenyloxyl, phenyl, alkylsulfonyl, C₁₋₆ alkenyl, —NH₂,—NHR⁷, —NR⁷R⁸, C₁₋₆ alkylcarboxyl, formyl, —NH—CO—C₁₋₆ alkyl, —CO—NR⁷R⁸,or SR⁷ wherein each of R⁷ and R⁸ is independently H or C₁₋₆ alkyl;

[0028] (2)1-naphthyl or 2-naphthyl that is unsubstituted or optionallymono- or poly-substituted with halogen, C₁₋₆ alkyl, CF₃, hydroxyl, C₁₋₆alkoxyl, OCF₃, CN, NO₂, phenyloxyl, phenyl, alkylsulfonyl, C₁₋₆ alkenyl,—NH₂, —NHR⁷, —NR⁷R⁸, C₁₋₆ alkylcarboxyl, formyl, —NH—CO—C₁₋₆ alkyl,—CO—NR⁷R⁸, or SR⁷ wherein each of R⁷ and R⁸ is independently H or C₁₋₆alkyl;

[0029] (3) cynnamoyl;

[0030] (4) benzyl;

[0031] (5) 1,1-diphenylethyl;

[0032] (6) a monocyclic or bicyclic heterocyclic ring selected from thegroup consisting of firyl, pyrrolyl, triazolyl, diazolyl, oxazolyl,thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl,pyrimidyl, pyrazinyl, thienyl, imidazolyl, pyrazolyl, indolyl,quinolinyl, isoquinolinyl, benzofuryl, benzothienyl, andbenzoxadiazolyl, said heterocyclic ring being optionally mono- ordi-substituted substituted with halogen or C₁₋₆ alkyl;

[0033] R⁴ is H or is selected from the group consisting of:

[0034] wherein R⁶ is H, C₁₋₆ alkyl, or benzyl; and

[0035] R⁵ is H, hydroxy, C₁₋₃ alkoxy, F, NO₂, CF₃, OCF₃ or is selectedfrom the group consisting of:

[0036] In another preferred embodiment, the invention features acompound of formula (I), supra, wherein

[0037] Ar is

[0038] (1) phenyl,

[0039] (2) 1-naphthyl or 2-naphthyl,

[0040] (3) a 5- to 10-membered monocyclic or bicyclic heterocyclic ringhaving 1 to 4 heteroatoms selected from the group consisting of oxygen,sulfur, or nitrogen, or

[0041] (4) —R⁹-phenyl;

[0042] wherein the phenyl, naphthyl, or heterocyclic ring is optionallysubstituted with F, Cl, Br, C₁₋₆ alkyl, CF₃, hydroxyl, C₁₋₆ alkoxyl,OCF₃, phenyl, C₂₋₆ alkenyl, —NR⁷R⁸, —NH—CO—C₁₋₆ alkyl, or SR⁷, whereineach of R⁷ and R⁸ is independently H or C₁₋₆ alkyl; and R⁹ is C₁₋₂alkyl;

[0043] R² is H, phenyl, I, or C₁₋₆ alkyl;

[0044] R⁴ is selected from the group consisting of:

[0045] R⁵ is C₁₋₃ alkoxy or a heterocyclic ring selected from the groupconsisting of:

[0046] Further preferred embodiments of the present invention areprovided below.

[0047] (1) Compounds of formula (I), supra, wherein wherein Ar isphenyl, optionally substituted with F, Cl, Br, methyl, CF₃, C₁₋₄alkoxyl, OCF₃, CN, NO₂, phenyloxy, phenyl, methylsulfonyl, or —NR⁷R⁸,where each of R⁷ and R⁸ is independently H or methyl.

[0048] (2) Compounds of formula (I), supra, wherein Ar is 1-naphthyl or2-naphthyl, each of which is optionally substituted with F, Cl, Br,methyl, CF₃, C₁₋₄ alkoxyl, OCF₃, CN, NO₂, phenyloxy, phenyl,methylsulfonyl, or —NR⁷R⁸, where each of R⁷ and R⁸ is independently H ormethyl.

[0049] (3) Compounds of formula (I), supra, wherein Ar is a heterocyclicring selected from the group consisting of furyl, pyrrolyl, triazolyl,diazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl,thiadiazolyl, pyridinyl, pyrimidyl, pyrazinyl, thienyl, imidazolyl,pyrazolyl, indolyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl,and benzoxadiazolyl, each of which is optionally substitiuted withhalogen, C₁₋₆ alkyl, CF₃, hydroxyl, C₁₋₆ alkoxyl, OCF₃, CN, NO₂,phenyloxy, phenyl, C₁₋₆ alkylsulfonyl, C₂₋₆ alkenyl, —NR⁷R⁸, C₁₋₆alkylcarboxyl, formyl, —NH—CO—C₁₋₆ alkyl, —CO—NR⁷R⁸, or SR⁷; whereineach of R⁷ and R⁸ is independently H or Cl ₆ alkyl.

[0050] (4) Compounds of formula (I), supra, wherein Ar is a heterocyclicring selected from the group consisting of pyridinyl, thienyl,imidazolyl, pyrazolyl, benzothienyl, and benzoxadiazolyl, each of whichis optionally substituted with halogen or C₁₋₆ alkyl.

[0051] (5) Compounds of formula (I), supra, wherein Ar is 2-pyridyl,3-pyridyl, or 4-pyridyl.

[0052] (6) Compounds of formula (I), supra, wherein Ar is a 5- to7-membered aromatic, partially saturated, or completely saturatedheterocyclic ring having 1 to 4 heteroatoms selected from the groupconsisting of O, S, or NR¹⁰, where R¹⁰ is H, C₁₋₆ alkyl, —CO—CF₃, orabsent.

[0053] (7) Compounds of formula (I), supra, wherein Ar is —R⁹-phenyl,wherein R⁹ is C₁₋₃ alkyl or C₂₋₃ alkenyl, either of which is optionallysubstituted with phenyl or phenyloxy, each phenyl being optionallysubstituted with F, Cl, Br, methyl, CF₃, ClO₄ alkoxyl, OCF₃, CN, NO₂,phenyloxy, phenyl, methylsulfonyl, or —NR⁷R⁸; and each of R⁷ and R⁸being independently H or C₁₋₆ alkyl.

[0054] Further preferred embodiments of the present invention includecompounds of formula (I), supra, wherein each of R² and R³ is H; andcompounds of formula (I), supra, wherein each of R⁴ and R⁵ isindependently H or a heterocyclic ring selected from the groupconsisting of:

[0055] wherein R⁶ is H, C₁₋₃ alkyl, or benzyl.

[0056] Some preferred compounds of the invention are:

[0057] 1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indole,

[0058] 1-[(4-fluorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole,

[0059]1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-(1-piperazinyl)-1H-indole,

[0060] 3-(1-azabicyclo[2.2.2]oct-2-en-3-yl)-1-(phenylsulfonyl)-1H-indole

[0061] 5-methoxy-1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indole,

[0062] 4-(4-ethyl-1-piperazinyl)-1-(phenylsulfonyl)-1H-indole,

[0063]1-[(4-methylphenyl)sulfonyl]-4-(4-methyl-1-piperazinyl)-1H-indole,

[0064] 1-(phenylsulfonyl)-5-(1-piperazinyl)-1H-indole,

[0065] 4-(2,5-dimethyl-1-piperazinyl)-1-(phenylsulfonyl)-1H-indole,

[0066] 4-(2,6-dimethyl-1-piperazinyl)-1-(phenylsulfonyl)-1H-indole,

[0067] 4-(1 ,4-diazepan-1-yl)-1-(phenylsulfonyl)-1H-indole,

[0068]2-[1-(phenylsulfonyl)-1H-indol-4-yl]octahydropyrrolo[1,2-a]pyrazine1-(2-naphthylsulfonyl)-4-(1-piperazinyl)-1H-indole,

[0069] 1-(1-naphthylsulfonyl)-4-(1-piperazinyl)-1H-indole,

[0070] 1-[(4-methylphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole,

[0071]N-(1-Azabicyclo[2.2.2]oct-3-yl)-N-{1-[(4-methylphenyl)sulfonyl]-1H-indol-4-yl}amine,

[0072] 2-Ethyl-4-(4-ethyl-1-piperazinyl)-1-[(phenyl)sulfonyl]-1H-indole,

[0073] 2-ethyl-1-(4-methyl-phenylsulfonyl)-4-(1-piperazinyl)-1H-indole,

[0074]4-(2,5-dimethyl-1-piperazinyl)-2-ethyl-1-(phenylsulfonyl)-1H-indole,

[0075]4-(4-ethyl-1-piperazinyl)-5-fluoro-1-[(4-methylphenyl)sulfonyl]-1H-indole,

[0076]5-fluoro-4-(1-piperazinyl)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-indole,

[0077] 5-chloro-1-phenylsulfonyl)-4-(1-piperazinyl)-1H-indole,5-chloro-1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indole,

[0078]1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-5-methoxy-4-(1-piperazinyl)-1H-indole,

[0079]1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-5-(1-piperazinyl)-1H-indole,

[0080]1-[(4-methylphenyl)sulfonyl]-4-(3-methyl-1-piperazinyl)-1H-indole,

[0081] 1-[(4-methylphenyl)sulfonyl]-4-(4-piperidinyloxy)-1H-indole, and

[0082]1-[(4-methylphenyl)sulfonyl]-4-(3-methyl-1-piperazinyl)-1H-indole.

[0083] Most preferred embodiments of the invention are the compounds

[0084] 1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indole hydrochloride,

[0085] 1-[(2,5-dimethoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride, and

[0086] 4-(1-piperazinyl)-1-(3-pyridinylsulfonyl)-1H-indolehydrochloride.

[0087] Certain compounds of formula (I) are capable of existing instereoisomeric forms including diastereomers and enantiomers and theinvention extends to each of these stereoisomeric forms and to mixturesthereof including racemates. The different stereoisomeric forms may beseparated from each other by conventional methods. Any given isomer maybe obtained by stereospecific or asymmetric synthesis. The inventionalso extends to any tautomeric forms and mixtures thereof.

[0088] The compounds of the formula (I) can form acid addition saltswith acids such as conventional pharmaceutically acceptable acids, forexample maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric,salicylic, citric, lactic, mandelic, tartaric and methanesulfonic.

[0089] Compounds of formula (I) may also form solvates such as hydratesand the invention also extends to these forms. When referred to herein,it is understood that the term “compound of formula (I)” also includesthese forms.

[0090] The compounds according to formula (I) can conveniently beadministered in a pharmaceutical composition containing the compound incombination with pharmacologically and pharmaceutically acceptablecarriers. Such pharmaceutical compositions can be prepared by methodsand contain carriers or excipients which are well known in the art. Agenerally recognized compendium of such methods and ingredients isRemington's Pharmaceutical Sciences by E.W. Martin (Mark Publ. Co.,15^(th) Ed., 1975). The compounds and compositions can be administeredorally, parenterally (for example, by intravenous, intraperitoneal orintramuscular injection), transdermally, or rectally.

[0091] For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

[0092] The tablets, troches, pills, capsules, and the like may alsocontain the following: binders such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, fructose, lactose or aspartame or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring may beadded. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fructose as asweetening agent, methyl and propylparabens as preservatives, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any unit dosage form should be pharmaceutically acceptableand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand devices.

[0093] The compounds or compositions can also be administeredintravenously, or intraperitoneally by infusion or injection. Solutionsof the active compound or its salts can be prepared in water, optionallymixed with a nontoxic surfactant. Dispersions can also be prepared inglycerol, liquid polyethylene glycols, triacetin, and mixtures thereofand in oils.

[0094] Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

[0095] The compound can be administered in unit dosage form; forexample, containing about 0.05 mg to about 500 mg, conveniently about0.1 Img to about 250 mg, most conveniently, about 1 mg to about 150 mgof active ingredient per unit dosage form. The desired dose may bepresented in a single dose or as divided doses administered atappropriate intervals.

[0096] The compositions can be administered orally, sublingually,transdermally, or parenterally at dose levels of about 0.01 to about 150mg/kg, preferably about 0.1 to about 50 mg/kg, and more preferably about0.1 to about 30 mg/kg of mammal body weight. TABLE I Compounds preparedaccording to synthetic schemes 1 or 2. All compounds in Table I arehydrochlorides salts.

EXAMPLE —SO₂—Ar R⁴ (7) 1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indole

(8) 1-[(2,5-dimethoxyphenyl)sulfonyl]-4-(1-piperazinyl)- 1H-indole

(9) 1-(mesitylsulfonyl)-4-(1-piperazinyl)-1H-indole

(10) 1-(1-naphthylsulfonyl)-4-(1-piperazinyl)-1H-indole

(11) N,N-dimethyl-N-(5-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}-1-naphthyl)amine

(12) 1-[(4-Propoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H- indole

(13) 1-[(2,5-Dichloro-3-thienyl)sulfonyl]-4-(1- piperazinyl)-1H-indolehydrochloride

(14) 1-[(4-Methoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H- indolehydrochloride

(15) 1-[(2,4-Difluorophenyl)sulfonyl]-4-(1-piperazinyl)- 1H-indolehydrochloride

(16) 1-([1,1′-Biphenyl]-4-ylsulfonyl)-4-(1-piperazinyl)-1H- indolehydrochloride

(17) 1-[(3,4-Dimethoxyphenyl)sulfonyl]-4-(1-piperazinyl)- 1H-indolehydrochloride

(18) 5-Methyl-2-methoxyl-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenyl ether hydrochloride

(19) 1-[(2,5-Dichlorophenyl)sulfonyl]-4-(1-piperazinyl)- 1H-indolehydrochloride

(20) 1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride

(21) 1-[(3-Chloro-2-methylphenyl)sulfonyl]-4-(1- piperazinyl)-1H-indolehydrochloride

(22) 2-Chloro-5-(4-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenoxy)benzonitrile hydrochloride

(23) 4-Bromo-2-{[4-(1-piperazinyl)-1H-indol-1- yl]sulfonyl}phenyl methylether hydrochloride

(24) 4-(1-Piperazinyl)-1-(3-pyridinylsulfonyl)-1H-indole hydrochloride

(25) 7-{[4-(1-Piperazinyl)-1H-indol-1-yl]sulfonyl}-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

(26) Methyl 2-{[4-(1-piperazinyl)-1H-indol-1- yl]sulfonyl}phenyl sulfonehydrochloride

(27) 1-[(4-fluorophenyl)sulfonyl]-4-(1-piperazinyl)-1H- indole

(28) 1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride

(29) 1-[(4-methylphenyl)sulfonyl]-4-(4-methyl-1- piperazinyl)-1H-indole

(32) 4-piperazine-N-(4- trifluoromethyl)phenylsulfonyl)indolehydrochloride

(33) 4-(3-methyl-1-piperazinyl)-1-{([4-(trifluoromethyl)phenyl]sulfonyl}-1H-indole

(36) 1-[(2-methylphenyl)sulfonyl]-4-(4-methyl-1- piperazinyl)-1H-indole

(37) 4-(4-ethyl-1-piperazinyl)-1-[(2- methylphenyl)sulfonyl]-1H-indole

(38) 1-[(2-methylphenyl)sulfonyl]-4-(1-piperazinyl)-1H- indole

(39) 4-(5-aza-indolizidinyl)-1-(2-methylbenzenesulfonyl)- 1H-indole

(40) 4-(4-methyl-1,4-diazepan-1-yl)-1-[(2-methylphenyl)sulfonyl]-1H-indole

(41) 4-(3-Methyl-1-piperazinyl)-1-(2- methylbenzenesulfonyl)-1H-indole

(42) 4-(3,5-dimethyl-1-piperazinyl)-1-[(2-methylphenyl)sulfonyl]-1H-indole

(43) 4-(4-isopropyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole

(44) 4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptyl)-1-(2-methylbenzenesulfonyl)-1H-indole

(45) 4-(4-methyl-1-homopiperazinyl)-1-(benzenesulfonyl)- 1H-indole

(46) 4-(cis 3,5-dimethyl-1-piperazinyl)-1- (benzenesulfonyl)-1H-indole

(47) 4-(4-ethyl-1-piperazinyl)-1-(benzenesulfonyl)-1H- indole

(62) 1-[(N-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride

(48) 4-Piperazinyl-1-(4-nitro-benzenesulfonyl)-1H-indole

(49) 4-Piperazinyl-1-(4-nitro-benzenesulfonyl)-1H-indole

(50) 4-Piperazinyl-1-(4-chloro-benzenesulfonyl)-1H-indole

(51) 4-Piperazinyl-1-(E2-phenyl-ethensulfonyl)-1H-indole

(52) 4-Piperazinyl-1-(3-trifluoromethyl-benzenesulfonyl)- 1H-indole

(53) 4-Piperazinyl-1-(4-cyanobenzenesulfonyl)-1H-indole

(54) 4-Piperazinyl-1-(4-chloro-7-sulfonyl-2,1,3- benzoxadiazolesulfonyl)-1H-indole

(55) 4-Piperazinyl-1-(3-cyanobenzenesulfonyl)-1H-indole

(56) 4-Piperazinyl-1-(4-phenoxybenzenesulfonyl)-1H- indole

(57) 4-Piperazinyl-1-(4-chlorophenylmethanesulfonyl)-1H- indole

(58) 4-Piperazinyl-1-(4-methylphenylmethanesulfonyl)- 1H-indole

(59) 4-Piperazinyl-1-(1,1-diphenylethanesulfonyl)-1H- indole,

(60) 4-Piperazinyl-1-(4-trifluoromethoxybenzenesulfonyl)- 1H-indole

(61) 4-Piperazinyl-1-(5-[(benzoylamino)methyl]thiophene-2-sulfonyl)-1H-indole

[0097] General Synthetic Schemes

[0098] The products described in the following examples were confirmedby standard spectroscopical methods and elemental analysis and/or highresolution MS. NMR spectra were obtained on Bruker 500 MHz or JEOL 270MHz spectrometers at 25° C., and the chemical shift values are reportedas parts per million (δ). MS spectra were acquired on a 2690 SeparationModule (Waters) with a Platform LCZ (Micromass). Flash chromatographywas performed on Silica gel 60 (Merck) or LiChroprep RP-18 (Merck). HPLCanalyses were accomplished on a HP Series1 100, with a GROM-SIL 100ODS-0 AB column, 4.6×50 mm. The HPLC purifications were performed onpreparative HPLC/ Mass system using YMC Combi prep ODS-AQ column, 56×20mm, Gilson pumps, Dynamax UV-1 detector and Finnigan Mass detector. Theeluents used were H₂O and CH₃CN, both with 0.1% TFA. The purity of thecompounds was determined by HPLC. Elemental analysis was performed atStructural Chemistry Department, Biovitrum AB, Stockholm. Meltingpoints, when given, were obtained on a Butchi or a Gallenkamp meltingpoint apparatus and are uncorrected.

[0099] General Synthetic Methods

[0100] Method 1: Buchwald Coupling Between Aryltriflates or Arylahalidesand Amines

[0101] To a solution of the aryltriflate (1 equiv.) in xylene are added,under N₂ flush, Pd(OAc)₂ (0.6 equiv.),(R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.1 equiv.) andCs₂CO₃ (3 equiv.), followed by amine (2 equiv.). The mixtures are heatedto 100° C.-120° C. under stirring (TLC monitoring). Purification byflash chromatography [SiO₂, CHCl₃ to MeOH:CHCl₃:aq NH₃ (10:90: 0.4%)]afforded the final compounds. The final compounds are converted intotheir hydrochloride salts by dissolving the free bases in methanol anddiethyl ether (1:9) followed by the addition of HCl in diethyl ether.

[0102] Method 2: Buchwald Coupling Between Arylhalides and Amines

[0103] To a mixture of 4-bromoindoles (1 equiv), t-Bu₃P (0.05 equiv.) or2-(dicyclohexylphosphino)biphenyl (0.05 equiv.), and Pd (OAc)₂ (0.02equiv.) in xylene are added amines (2.8 equiv.) and NaOt-Bu (2.8equiv.). The reactions are heated at 120° C. for 4 h, filtered throughcelite and the solvent is removed. The crude mixtures are purified bycolumn chromatography (SiO₂, CH₂Cl₂/heptane 1:4) to yield finalcompounds. The final compounds are converted in their hydrochloridesalts according to the same procedure as described in Method 1.

[0104] Method 3: Sulfonylation in the Presence of NaOH

[0105] Arylsulfonyl chlorides (0.75 rumol) are added to a cold (0° C.)solution of indole derivates (0.5 mmol), grounded NaOH (3 mnmol) andtetrabutyl ammonium hydrogen sulfate (0.05 mmol) in CH₂Cl₂ (3 mL). Themixtures are shaken for 30 min at 0° C. and 30 min at room temperature.Each mixture is then filtered through a bed of hydromatrix (Varian; 3cm) and silica gel (0.5 cm). The system is washed with CH₂Cl₂ (2×3 mL)and the solvent is evaporated in vacuum. The resulting residues (finalproducts as free base) are dissolved in CH₂Cl₂ (3 mL) and HCl in etheris added (2 mL) and shaken for 2 h at room temperature. The resultingprecipitates are collected by filtration to give the final compounds ashydrochloride salts. The purity of the compounds is analyzed by LC andeventually purified by LC/MS if required. Method 4: Sulfonylation in thepresence of NaH Sulfonylchlorides (1.5 equiv.) are added to indolesderivatives (lequiv.) and NaH 60% dispersion in oil (2 equiv.) in CH₂Cl₂containing DMF (1%). After 1 h at room temperature the reactions arequenched with water, filtered and the solvent is removed. Purificationby column chromatography (SiO₂, CH₂Cl₂:MeOH 9:1:0.4% NH₃) gave the finalcompounds. The final compounds are transformed into their hydrochloridesalts by the procedure described in Method 1.

[0106] Method 5: Sulfonylation of sodium salt of4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stock solution A). NaH (163mg, 6.5 mmol) is added to a solution of4-(4-t-butyloxycarbonyl)-piperazinyl-indole (1.50 g, 6.50 mmol) in THF(45 mL). The reaction is stirred at room temperature for 0.5 h. Thesuspension is diluted to 60 mL with THF and distributed into 30 reactionvials (stock solution A). Diverse sulfonylchlorides (0.25 mmol) in THF(2 mL) are added to the stock solution A (2 mL). The reactions areshaken for 3 h followed by addition of MeOH (100 μL).Polystyrene-trisamine (PS-trisamine) is added to the mixtures and thereactions are agitated at room temperature over night. The mixtures arefiltered through a short silica column and the volatiles are removed.The crude products are dissolved in MeOH (2 mL) followed by addition ofHCl/ether 2 M (4 mL). After 0.5 h the sample was centrifugated and thesupernatant was decanted after 0.5 hrs. The remaining solid was washedwith (ether) and dried in vacuo to afford the hydrochloride salts.

EXAMPLE 1 Intermediate

[0107] 4-Bromo-1-(tri-isopropylsilyl)-1H-indole (Scheme 1)

[0108] The NaH 60% dispersion in oil (0.94 g, 23.4 mmol) was added to asolution of 4-bromoindole (3.07 g, 15.6 mmol) and triisopropylsilylchloride (3.62 g, 18.8 mmol) in CH₂Cl₂ (50 mL) and DMF (2 mL). Thereaction was stirred at room temperature for 1 h and quenched withwater. The insoluble material was filtered off and the solvent wasremoved. Purification by column chromatography (SiO₂, CH₂Cl₂/heptane1:4) yielded 3.44 g (63%) of the title compound: ¹H NMR (CDCl₃) δ7.42-6.63 (m, 5H), 1.66 (sept, J=8 Hz, 3H), 1.10 (d, J=8 Hz, 18H; MS(ESI) 354.4 (M+H)⁺; Purity (HPLC) >95%.

EXAMPLE 2 Intermediate

[0109] N-tert-Butyl-trimethylsilyl-4-chloroindole (Scheme 1)

[0110] 4-Chloroindole (131.1 g, 0.871 mol) was dissolved in dry THF (0.5L). The solution was chilled to 0° C. (ice bath, stirring). t-BuOK (97.6g, 0.871 mol) was added in one portion and the stirring was continuedfor additional 5 minutes. Tert-butyldimethylchlorosilane (131 .3 g,0.871 mol) was added portionwise over 10 min with a good stirring. Thereaction is exothermic. After 30 minutes the reaction was quenched withwater (20 ml) and pH was adjusted to 8-9 and extracted with ethylacetate (3×50 mL). The organic phases were dried (MgSO₄), filtered andthe volatiles were eliminate by vacuum. The residue was triturated andcrystallized from heptane to yield 181 g (78%) of the title compound. ¹HNMR (CDCl₃) 6 7.45 (dd, J=7.9 Hz, J==0.8 Hz, 1H), 7.25 (d, J=3.0 Hz,1H), 7.18-7.07 (m, 2H), 6.77 (d, 1H), 0.96 (s, 9H), 0.62 (s, 6H); ¹³CNMR (CDCl₃) 141.8; 131.7; 130.3; 125.9; 122.0; 119.7; 112.5; 103.5;26.3; 19.5;-3.9; MS (ESI) 266.1 (M+H).

EXAMPLE 3 Intermediate

[0111] 4-(4-Methyl-1-Piperazinyl)-1-(triisopropylsilyt)-1H-indole(Scheme 1)

[0112] The compound was prepared according to Method 2 from4-bromo-1-(triisopropylsilyl)indole (0.090 g, 0.255 mmol), t-Bu₃P (3.6mg, 0.014 mmol), and Pd (OAc)₂ (1 mg, 0.0036 mmol) in xylene (3 mL) and4-methyl-1-piperazine (0.135 g, 0.73 mmol) and NaOt-Bu (69 mg, 0.72mmol). The crude was purified by column chromatography (SiO₂,CH₂Cl₂/heptane 1:4) to yield 90 mg (84%) of pure material: ¹H NMR(CD₃OD) δ 7.19-6.56 (m, 5H), 3.31-3.25 (m, 4H), 2.71-2.63 (m, 4H), 2.36(s, 3H), 1.76 (sept, J=8 Hz, 3H), 1.1 (d, J=8 Hz, 18H); MS (ESI) 372.5(M+H)⁺; Purity (HPLC) >95%.

EXAMPLE 4 Intermediate

[0113] N-tert-Butyldimethylsilyl-4-(4-Boc-piperazinyl)-indole (Scheme 1)

[0114] The compound was prepared according to Method 2 fromN-tert-butyldimethylsilyl -4-chloroindole (100 g, 376 mmol, 1 equiv.),tert-butyl 1-piperazinecarboxylate (84 g, 451 mmol), Palladium(II)acetate (1.26 g., 5.62 mmol, 2%), 2-(dicyclohexylphosphino)biphenyl(3.95 g., 11.28 mmol, 4 mol %), tert-BuONa (50 g, 520 mmol, 1.4 equiv.)in toluene. The solution was cooled to room temperature and KH₂PO₄ (150mL, 13% aqueous solution) was added and pH was adjusted (pH=8-9 )followed by extraction with toluene (2×100 mL), dried (MgSO₄) andevaporated. The residue was crystallized from heptane to yield 124.4 g(79.6%). ¹H NMR (CDCl₃) δ 7.20 (d, J=8.4 Hz, 1H), 7.13 (d, J=3.2 Hz,1H), 7.06 (t, 1H), 6.60-6.57 (m, 2H), 3.65 (t, 4H), 3.16 (t, 4H), 1.48(s, 9H), 0.91 (s, 9H), 0.58 (s, 6H); ¹³C NMR (CDCl₃) δ 155.0; 145.5;142.2; 129.9; 124.9; 122.0; 109.3; 107.2; 102.9; 79.8; 77.3; 51.5; 28.5;26.4; 19.5; −3.8; MS (ESI) 416.4 (M+H).

EXAMPLE 5 Intermediate

[0115] 4-(4-Boc-piperazinyl)-indole (Scheme 1)

[0116] A mixture ofN-tert-butyldimethylsilyl-4-(4-tert-butyloxylcarbonate-piperazinyl)-indole(4) (116.9 g., 281 mmol), NaF (30 g., 714 mmol), AcOEt (440 g), water(200 mL) and Bu4NSO₄ (2 g, 6 mmol) was heated under powerful stirring at50-60° C. under N₂ for 2 h. The organic phase was separated and thewater phase was extracted once more by AcOEt (100 mL). The organicphases were dried (MgSO₄), evaporated and co-evaporated with ethanol.The residue was crystallized from ether:hexane (1:3) to yield 81.0 g(95.6%) of the title compound. ¹H NMR (CDCl₃) δ 8.59 (bs, 1H); 7.12-7.02(m, 3H), 6.58 (d, J=6.9 Hz, 1H), 7.53 (t, 1H), 3.69 (t, 4H), 3.19 (t,4H), 1.53 (s, 9H); ¹³C NMR (CDCl₃) δ 155.1; 145.5; 137.1; 123.2; 122.6;121.4; 106.9; 106.5; 100.8; 80.0; 77.4; 51.4; 28.6; MS (ESI) 302.2(M+H).

EXAMPLE 6 Intermediate

[0117] 4-(4-Methyl-1-piperazinyl)-1H-indole (Scheme 1)

[0118] A mixture of4-(1-methyl-1-piperazinyl)-1-(triisopropylsilyl)-1H-indole (110 mg,0.296 mmol) and Bu4NF IM in THF (1 mL) was stirred at room temperaturefor 1 h. A mixture of CH₂Cl₂/heptane 1:1 (10 mL) was added followed byfiltration through silica. The product was purified by columnchromatography (SiO₂, CH₂Cl₂:MeOH 9:1:0.4% NH₃) to yield 60 mg (94%) ofthe title product: ¹H NMR (CD₃OD) 6 7.11-6.41 (m, 5H), 3.30-3.23 (m,4H), 2.71-2.66 (m, 4H), 2.37 (s, 3H); MS (ESI) 216.4 (M+H)⁺; Purity(HPLC) >95%.

EXAMPLE 7

[0119] 1-Phenylsulfonyl-4-piperazinylindole Dihydrochloride

[0120] The title compound was prepared from 4-boc-piperazinyl-indole andphenylsulfonylchloride according to Method 3: ¹H NMR (DMSO-d₆) δ 9.64(brs, 2H), 7.98-7.94 (m, 4H), 7.80-7.77 (m, 1H), 7.70-7.65 (m, 1H),7.63-7.55 (m, 3H), 7.27-7.22 (m, 1H), 6.95 (d, J=3.76 Hz, 1H), 6.81-6.77(m, 1H), 3.31-3.20 (m, 4H); ³C NMR (DMSO-d₆) δ 144.79, 137.02, 135.22,134.62, 129.82, 126.65, 125.63, 125.54, 123.49, 111.15, 107.87, 107.76,47.81, 42.86. Anal. (C₁₈H₁₉N₃O₂S₂HCl 0.5 H₂O) C, H, N.

EXAMPLE 8

[0121] 1-[(2,5-Dimethoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indoleHydrochloride (Scheme 1)

[0122] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 2,5-dimethoxyphenyl)sulfonyl chloride according to Method 3: ¹H NMR(500 MHz, DMSO-d₆) δ 8.95 (br, 1H), 7.71 (d, J=5 Hz, 1H), 7.52 (d, J=5Hz, 1H), 7.38 (d, J=8 Hz, 1 H), 7.27 (d, J=8 Hz, 1H), 7.14 (t, J=8 Hz,1H), 7.13 (d, J=8 Hz, 1H), 6.86 (d, J=5 Hz, 1H), 6.77 (d, J=8 Hz, 1H),3.81 (s, 3H), 3.64 (s, 3H), 3.40-3.20 (m, 8H); MS (ESI+) for m/z 402(M+H)⁺.

EXAMPLE 9

[0123] 1-(Mesitylsulfonyl)-4-(1-piperazinyl)-1H-indole Hydrochloride(Scheme 1)

[0124] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand mesitylsulfonylchloride according to Method 3: 1H NMR (270 MHz,DMSO-d₆) δ 9.10 (br, 1H), 7.71 (d, J=5 Hz, 1H), 7.40-7.20 (m, 3H),7.00-6.80 (m, 2H), 6.51 (d, J=8 Hz, 1H), 3.30-3.20 (m, 8H), 2.41 (s,6H), 2.27 (s, 3H); MS (ESI+) for m/z 384 (M+H)⁺.

EXAMPLE 10

[0125] 1-(1-Naphthylsulfonyl)-4-(1-piperazinyl)-1H-indole Hydrochloride(Scheme 1)

[0126] The title compound was prepared according4-(4-boc-piperazinyl)-indole and naphthylsulfonylchloride according toMethod 3: ¹H NMR (270 MHz, DMSO-d₆) δ 9.03 (br, 1H), 8.63 (d, J=8 Hz,1H), 8.43 (d, J=8 Hz, 1H), 8.34 (d, J=8 Hz, 1H), 8.15-8.05 (m, 2H),7.80-7.65 (m, 3H), 7.41 (d, J=8 Hz, 1H), 7.18 (t, J=8 Hz, 1H), 6.93 (d,J=5Hz, 1H), 6.74 (d, J=8Hz, 1H), 3.30-3.20 (m, 8H); MS (ESI+) for m/z392 (M+H)⁺.

EXAMPLE 11

[0127]N,N-Dimethyl-5-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}-1-naphthalenaminehydrochloride (Scheme 1) The title compound was prepared from4-(4-boc-piperazinyl)-indole and5-N,N-dimethyl-naphthalenamine-1-sulfonylchloride according to Method 3:¹H NMR (270 MHz, DMSO-d₆) δ 9.25 (br, 1H), 8.63 (d, J=8 Hz, 1H), 8.41(d, J=8 Hz, 1H), 8.29 (d, J=8 Hz, 1H), 8.12 (m, 2H), 7.80-7.65 (m, 3H),7.41 (d, J=8 Hz, 1H), 7.18 (t, J=8 Hz, 1 H), 6.93 (d, J=5 Hz, 1H), 6.74(d, J=8 Hz, 1H), 3.30-3.20 (m, 8H), 2.82 (m, 6H); MS (ESI+) for m/z 435(M+H)⁺.

EXAMPLE 12

[0128] 1-[(4-Propoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indoleHydrochloride (Scheme 1)

[0129] The title compound was prepared according from4-(4-boc-piperazinyl)-indole and 4-propoxyphenylsylfonyl chlorideaccording to Method 3: ¹H NMR (270 MHz, DMSO-d₆) δ 9.03 (br, 1H), 7.89(d, J=8 Hz, 2H), 7.78 (d, J=5 Hz, 1H), 7.61 (d, J=8 Hz, 1H), 7.25 (t,J=8 Hz, 1H), 7.07 (d, J=8 Hz, 2H), 6.93 (d, J=5 Hz, 1H), 6.67 (d, J=8Hz, 1H), 4.01 (t, J=7 Hz, 2H), 3.28 (m, 8H), 1.66 (m, 2H), 1.38 (m, 2H),0,88 (t, J=7 Hz, 2H). MS (ESI+) for m/z 414 (M+H)⁺.

EXAMPLE 13

[0130] 1-[(2,5-Dichloro-3-thienyl)sulfonyl]-4-(1-piperazinyl)-1H-indoleHydrochloride (Scheme 1)

[0131] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 2,5-dichloro-3-thienylsulfonyl chloride according to Method 3: ¹HNMR (270 MHz, DMSO-d₆) δ 9.24 (br, 1H), 7.78 (d, J=5 Hz, 1H), 7.72 (s,1H), 7.57 (d, J=8 Hz, 1H), 7.29 (t, J=8 Hz, 1H), 7.01 (d, J=5 Hz, 1H),6.86 (d, J=8 Hz, 1H), 3.31 (m, 8H). MS (ESI+) for m/z 416 (M+H)⁺.

EXAMPLE 14

[0132] 1-[(4-Methoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indoleHydrochloride (Scheme 1)

[0133] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 4-methoxyphenylsulfonyl chloride according to Method 3: ¹H NMR (270MHz, DMSO-d₆) δ 9.07 (br, 1H), 7.90 (d, J=8 Hz, 2H), 7.78 (d, J=5 Hz,1H), 7.61 (d, J==8 Hz, 1H), 7.25 (t, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 2H),6.92 (d, J=5 Hz, 1H), 6.68 (d, J=8 Hz, 1H), 3.79 (s, 3H), 3.24 (m, 8H);MS (ESI+) for m/z 371 (M+H)⁺.

EXAMPLE 15

[0134] 1-[(2,4-Difluorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-indoleHydrochloride (Scheme 1)

[0135] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 2,4-di-fluorophenylsulfonylchloride according to Method 3: ¹H NMR(270 MHz, DMSO-d₆) δ 9.41 (br, 1H), 8.24 (m, 1H), 7.75 (m, 1H), 7.58 (m,1H), 7.47-7.33 (m, 2H), 7.23 (t, J=8 Hz, 1H), 6.99 (d, J=5 Hz, 1H), 6.70(d, J -8 Hz, 1H), 3.25 (m, 8H). MS (ESI+) for m/z 378 (M+H)⁺.

EXAMPLE 16

[0136] 1-([1,1′-Biphenyl]-4-yl-sulfonyl)-4-(1-piperazinyl)-1H-indoleHydrochloride (Scheme 1)

[0137] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 1,1 ′-biphenyl-4-ylsulfonyl chloride according to Method 3: ¹H NMR(270 MHz, DMSO-d₆) δ 9.26 (br, 1H), 8.04 (m, 2H), 7.88 (m, 3H), 7.67 (m,3H), 7.46 (m, 3H), 7.27 (t, J=8 Hz, 1H), 6.96 (d, J=5 Hz, 1H), 6.80 (d,J=8 Hz, 1H), 3.25 (m, 8H); MS (ESI+) for m/z 418 (M+H)⁺.

EXAMPLE 17

[0138] 1-[(3,4-Dimethoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indoleHydrochloride (Scheme 1)

[0139] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 3,4-dimethoxyphenylsulfonyl chloride according to Method 3: ¹H NMR(270 MHz, DMSO-d₆) δ 9.00 (br, 1H), 7.82 (d, J=5 Hz, 1H), 7.66 (d, J=8Hz, 1H), 7.57 (m, 1H), 7.40 (d, J=3 Hz, 1H), 7.24 (t, J=8 Hz, 1H), 7.10(d, J=8 Hz, 1H), 6.90 (d, J=5 Hz, 1H), 6.78 (d, J=8 Hz, 1H), 3.78 (s,6H), 3.24 (m, 8H); MS (ESI+) for m/z 402 (M+H)⁺.

EXAMPLE 18

[0140]5-Methyl-2-methoxyl-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenylEther Hydrochloride (Scheme 1)

[0141] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 5-methyl-2-methoxyphenylsulfonyl chloride according to Method 3: ¹HNMR (270 MHz, DMSO-d₆) δ 9.45 (br, 1H), 7.92 (d, J=8 Hz, 1H), 7.70 (d,J=5 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 7.13 (t,J=8Hz, 1H), 7.01-6.92 (m,2H), 6.83 (d,J=5Hz, 1H), 6.73 (d,J=8Hz, 1H), 3.70 (s, 3H), 3.26 (m, 8H),3.32 (s, 3H); MS (ESI+) for m/z 386 (M+H)⁺.

EXAMPLE 19

[0142] 1-[(2,5-Dichlorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride (Scheme 1)

[0143] The title compound was prepared according from4-(4-boc-piperazinyl)-indole and 2,5-dichlorophenylsulfonyl chlorideaccording to Method 3: ¹H NMR (270 MHz, DMSO-d₆) δ 9.09 (br, 1H), 8.25(d, J=3 Hz, 1H), 7.91-7.81 (m, 2H), 7.72 (d, J=8 Hz, 1H), 7.36 (d, J 8Hz, 1H), 7.23 (t, J=8 Hz, 1H), 6.98 (d, J 3 Hz, 1H), 6.82 (d, J=8 Hz,H), 3.26(m,8H).

EXAMPLE 20

[0144]1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(1-piperazinyl)-1H-indoleHydrochloride (Scheme 1)

[0145] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 5-chloro-1,3-dimethyl-1H-pyrazol-4yl-sulfonyl chloride according toMethod 3: ¹H NMR (270 MHz, DMSO-d₆) δ 9.17 (br, 1H), 7.78 (d, J=3 Hz,1H), 7.49 (d, J=8 Hz, 1H), 7.28 (t, J=8 Hz, 1H), 6.93 (d, J=3 Hz, 1H),6.87 (d, J=8 Hz, 1H), 3.72 (s, 3H), 3.28 (m, 8H), 2.34 (s, 3H); MS(ESI+) for m/z 394 (M+H)⁺.

EXAMPLE 21

[0146] 1-[(3-Chloro-2-methylphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indoleHydrochloride (Scheme 1)

[0147] The compound was prepared from 4-(4-boc-piperazinyl)-indole and3-chloro-2-methoxylphenylsulfonyl chloride according to Method 3: ¹H NMR(270 MHz, DMSO-d₆) δ 9.21 (br, 1H), 7.89 (d, J=3 Hz, 1H), 7.82 (t, J=8Hz, 1H), 7.51 (t, J=8 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.10 (t, J=8 Hz,1H), 7.01 (d, J=3 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 3.29 (m, 8H), 2.54 (s,3H); MS (ESI+) for m/z 390 (M+H)⁺.

EXAMPLE 22

[0148]2-Chloro-5-(4-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenoxy)benzonitrileHydrochloride (Scheme 1)

[0149] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 2-chloro-5-[(4-(piperazinyl)-1H-indol-1-yl]-sulfonyl chlorideaccording to Method 3: ¹H NMR (270 MHz, DMSO-d₆) δ 9.20 (br, 1H), 8,06(d, J=8 Hz, 2H), 7.81 (d, J=3 Hz, 1H), 7.75-7.55 (m, 3H), 7.30-7.15 (m,4H), 6.97 (d, J=3 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 3.27 (m, 8H); MS (ESI+)for m/z 493 (M)⁺, 495.

EXAMPLE 23

[0150] 4-Bromo-2-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenylMethyl Ether Hydrochloride (Scheme 1)

[0151] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 4-bromo-2-phenylmethylethersulfonyl chloride according to Method 3:¹H NMR (270 MHz, DMSO-d₆) δ 9.40 (br, 1H), 8.12 (d, J=3 Hz, 1H), 7.88(d, J=8Hz, 1H), 7.72 (d, J=5 Hz, 1H), 7.37 (d, J=8 Hz, 1H), 7.25-7.10(m, 2H), 6.89 (d, J=3 Hz, 1H), 6.78 (d, J=8 Hz, 1H), 3.71 (s, 3H), 3.29(m, 8H); MS (ESI+) for m/z 450 (M)⁺, 452.

EXAMPLE 24

[0152] 4-(1-Piperazinyl)-1-(3-pyridinylsulfonyl)-1H-indole Hydrochloride(Scheme 1)

[0153] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 3-pyridinylsulfonyl chloride according to Method 3: ¹H NMR (270 MHz,DMSO-d₆) δ 9.37 (br, 1H), 9.18 (d, J=3 Hz, 1H), 8.86 (d, J=5 Hz, 1H),8.39 (d, J=8 Hz, 1H), 7.85 (d, J=3 Hz, 1H), 7.70-7.60 (m, 2H), 7.27 (t,J=8 Hz, 1H), 7.00 (d, J=3 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 3.24 (m, 8H);MS (ESI+) for m/z 343 (M+H)⁺.

EXAMPLE 25

[0154]7-{[4-(1-Piperazinyl)-1H-indol-1-yl]sulfonyl}-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolineHydrochloride (Scheme 1)

[0155] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolinsulfonyl chlorideaccording to Method 3: ¹H NMR (500 MHz, DMSO-d₆) The experiment was doneat 1000° C. 5 9.25 (br, 1H), 7.94 (br, 1H), 7.75 (d, J=8 Hz, 1H), 7.71(d, J=3 Hz, 1H), 7.63 (d, J=8 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 7.26 (t,J=8 Hz, 1H), 6.90 (d, J=3 Hz, 1H), 6.81 (d, J-8 Hz, 1H), 4.80 (s, 2H),3.79 (m, 2H), 3.35-3.25 (m, 8H), 2.97 (m, 2H); MS (ESI+) for m/z 493(M+H)⁺.

EXAMPLE 26

[0156] Methyl 2-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenylSulfone Hydrochloride (Scheme 1)

[0157] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 2-methylsulfonyl-phenylsulfonyl chloride according to Method 3: ¹HNMR (270 MHz, DMSO-d₆) δ 9.22 (br, 1H), 8.29 (d, J=-8 Hz, 1H), 7.99 (t,J=8 Hz, 1H), 7.90-7.80 (m, 2H), 7.43 (d, J=8 Hz, 1H), 7.3 0-7.15 (m,2H), 7.04 (d, J=3 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 3.56 (s, 3H), 3.29 (m,8H); MS (ESI+) for ml/z 420 (M+H)⁺.

EXAMPLE 27

[0158] 1-[(4-fluorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride (Scheme 1)

[0159] The title compound was prepared from 4-(4-boc-piperazinyl)-indoleand 2-methylsulfonyl-phenylsulfonyl chloride according to Method 4 yieldthe hydrochloride (yield 70%), HPLC purity >95%; ¹H NMR (DMSO-d₆) δ 3.26(bs, 8H), 6.80 (bs, 1H), 6.95 (bs, 1H), 7.26 (bs, 1H), 7.61 (app t, 2H),7.80 (bs, 1H), 8.06 (bs, 1H), 9.30 (bs, 1H); ¹³C NMR(DMSO-d₆) δ 165.20,144.94, 135.14, 133.31, 130.06(2C), 125.62(2C), 123.50, 117.25, 117.06,111.15, 107.92, 107.71, 47.82 (2C), 42.98 (2C); MS rosES-FIA) m/z 360(M+H).

EXAMPLE 28

[0160]1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-(1-piperazinyl)-1H-indoleHydrochloride (Scheme 1)

[0161] The title compound was prepared 4-(4-boc-piperazinyl)-indole and1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl chloride according toMethod 4 to afford the hydrochloride salt (yield 45%), HPLC purity >95%;¹H NMR (DMSO-d₆) δ 2.65 (s, 3H), 3.26 (bs, 8H), 6.82 (app d, 1H), 7.00(appd, 1H), 7.28 (app t, 1H), 7.60 (app dd, 2H), 7.87 (app d, 1H),8.08-8.12 (m, 2H); ¹³C NMR (DMSO-d₆) δ 145.05, 139.82, 139.35, 137.46,135.14, 133.31, 130.96, 128.70 (2C), 125.62, 124.89, 124.12, 123.52,111.42, 107.91, 107.71, 47.87 (2C), 43.03 (2C), 12.27; MS (posES-FIA)m/z 446 (M+H).

EXAMPLE 29

[0162] 4-(4-Methyl-1-piperazinyl)-1-(4-methylbenzenesulfonyl)-1H-indoleHydrochloride (Scheme 1)

[0163] The title compound was prepared4-(4-methyl-1-piperazinyl)-1H-indole and p-methylbenzenesulfonylchloride according to Method 4 (45%): ¹H NMR (CD₃OD) δ 7.81-6.77 (m,9H), 3.62-3.02 (m, 8H), 2.98 (s, 3H), 2.34 (s, 3H); MS (ESI) 370.5(M+H)⁺; Purity (HPLC) >95%.

EXAMPLE (INTERMEDIATE) 30

[0164] Synthesis of 4-(trifluoromethylsulfonyloxy)indole (Scheme 2)

[0165] Et₃N (1.6 mL, 11.3 mmol) was added to a solution of4-hydroxylindole (1.0 g, 7.5 mmol) in CH₂Cl₂ (20 mL). The reaction wascooled (ice bath) followed by the careful addition of a solutionN-phenyl-bis(trifluoromethanesulfonamide) (2.6 g, 7.5 nunol) in CH₂Cl₂.The reaction was washed with aqueous K₂CO₃ after 10 minutes, dried(K₂CO₃) and filtered. The volatiles were eliminated by vacuum to give2.9 g of a light brown oil that was purified by flash chromatography(SiO₂, CHCl₃). This gave 2.47g (62%) of the title product as a lightorange oil. Purity according to GC analysis was 92%. ¹H NMR (MeOH-d3): δ7.45 (d, 1H), 7.35 (d, 1H), 7.15 (t, 1H), 7.00 (d, 1H), 6.50 (d, 1H).

EXAMPLE (INTERMEDIATE) 31

[0166] Synthesis of4-(trifluoromethylsulfonyloxy)(N-(4-trifluoromethyl)phenylsulfonyl)indole(Scheme 2)

[0167] A solution of 4-(trifluoromethylsulfonyloxy)indole (2.28 g, 8.6mmol) in CH₂Cl₂ was added dropwise over 10 minutes to a mixture of NaH(619 mg, 25.8 mmol prewashed with heptane) in CH₂Cl₂ (20 mL) and DMF(0.5 mL) under N₂. A solution of 4-(trifluoromethyl)-benzenesulfonylchloride (2.31 g, 9.5 mmol) in CH₂Cl₂ (1 mL) was then added slowly at 0°C. The mixture was left at room temperature under stirring for 1 h. Thereaction was then quenched carefully with water, the organic phaseisolated, dried, filtered through silica and concentrated to yield 3.3 gcrude product as a red oil. The product was purified by flashchromatography (SiO₂, heptane to heptane/EtOAc 10:1 to yield 2.43 g(59%) of the title product as a colorless oil. HPLC analysis 100%. MSm/z=496 (M+Na+). ¹H NMR (MeOH-d3): δ 8.20 (d, 2H), 8.1 (d, 1H), 7.85 (m,3H), 7.45 (t, 1H), 7.30 (d, 1H), 6.85 (d, 1H).

EXAMPLE 32

[0168] 4-Piperazino-N-(4-trifluoromethyl)phenylsulfonyl)indoleHydrochloride (Scheme 2)

[0169] The title compound was prepared from4-(trifluoromethylsulfonyloxy)(N-(4-trifluoromethyl)-phenylsulfonyl)indole(200 mg, 0.42 mmol) and piperazine (72 mg, 0.84 mmol) according toMethod 1. Purification by flash chromatography (SiO₂, CHCl₃ toMeOH:CHCl₃ 10:90: 0.4% aq NH₃) afforded to 10 mg of a yellow oil. Thiswas dissolved in ethanol and HCl/ether was added and allowed to stir fora few hours. The solid was filtered to yield 10 mg final product as abeige solid that was further purified by preparative HPLC to give, afterformation of the HCl salt, the final product (38 mg, 51 %) as anoff-white solid. HPLC 97%. MS (posEI) m/z=410 (M+H). ¹H NMR (CD₃OD) δ8.12 (d, 2H,,J=8.3 Hz), 7.84 (d, 2H, J=8.3 Hz), 7.76-7.68 (m, 2H),7.33-7.27 (m, 1H), 6.88-6.85 (m, 2H) 3.44-3.30 (m, 8H, partly hidden).

EXAMPLE 33

[0170]4-(3-Methylpiperazine)-(N-(4-trifluoromethyl)phenylsulfonyl)indoleDihydrochloride (Scheme 2)

[0171] The title compound was prepared from4-(trifluoromethylsulfonyloxy)(N-(4-trifluoromethyl)-phenylsulfonyl)indoleand rac-2-methylpiperazine according to Method 1. Filtration throughsilica using CHCl₃ to MeOH:CHCl₃ 10:90: 0.4% aq NH₃ as eluent gave 48 mgof final product as a beige solid. mp 145° C. (dec); ¹H NMR (MeOH-d3): δ8.10 (d, 2H), 7.85 (d, 2H), 7.75 (d, 1H), 7.65 (d, 1H), 7.30 (t, 1H),6.85 (m, 2H), 3.50 (m, 5H), 3.00 (t, 1H), 2.85 (t, 1H), 1.35 (d, 3H);).HPLC 94%; MS (posEI) m/z-424 (M+H). Anal. (C₂₀H₂₀F₃N₃O₂S.2HCl) C,H,N,S.N calcd. 8.47, found 9.32.

EXAMPLE (Intermediate) 34

[0172] 4-Bromo-1-(benzenesulfonyl)-1H-indole (Scheme 2)

[0173] 4-Bromo-1-(benzenesulfonyl)-1H-indole was prepared from4-bromoindole and phenylsulfonyl chloride according to Method 4 toafford 3.1 g (91%) of a light purple solid: ¹HNMR (CDCl₃) δ 7.94 (d, J=8Hz, 1H), 7.89-7.84 (m, 2H), 7.62 (d, 4 Hz, 1H), 7.57-7.51 (m, 1H),7.46-7.37 (m, 3H), 7.19-7.13 (m, 1H), 6.72 (dd, J=1, 4 Hz, 1H); MS (ESI)419.9+421.9 (M+H)⁺; Purity (HPLC) >95%.

EXAMPLE (INTERMEDIATE) 35

[0174] 4-Bromo-1-(2-methyl-benzenesulfonyl)-1H-indole (Scheme 2)

[0175] The compound was prepared from 4-bromoindole (1.02 g, 5.25 mmol)and o-methylbenzenesulfonyl chloride (a 9:1 mixture of ortho and paramethyl isomers) (1.29 g, 6.78 mmol) according to method 4. Purificationby column chromatography (SiO₂, CH₂Cl₂:heptane) gave 1.6 g (87%) of thetitle compound which contains ca 10% of the p-methyl isomer) as a lightpurple viscous oil: ¹H NMR (CD₃OD) δ 7.94-6.68 (m, 9H), 2.52 (s, 3H); MS(ESI) 352.3 (M+H)⁺; Purity (HPLC) >95%.

EXAMPLE 36

[0176] 4-(4-Methyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole(Scheme 2)

[0177] The title compound was prepared from4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole (0.135 mg, 0.385 mmol)and 4-methyl-1-piperazine (0.143 mg, 0.77 mmol) according to Method 2.The product purified by flash column chromatography (SiO₂, CH₂Cl₂:MeOH9:1:0.4% NH₃) and converted into its HCl salt to afford 15 mg (10%):¹HNMR (CD₃OD) δ 7.97-6.79 (m, 9H), 3.72-3.07 (m, 8H), 3.01 (s, 31H),2.48 (s, 3H); MS (ESI) 370.0 (M+H)⁺; Purity (HPLC) >95%.

EXAMPLE 37

[0178] 4-(4-Ethyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole(Scheme 1)

[0179] The compounds was prepared from4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and 4-ethyl-1-piperazineaccording to Method 1. The product was isolated by column chromatography(SiO₂, CH₂Cl₂:MeOH/heptane:0.4% NH₃) and converted into itshydrochloride salt by addition of HCl/ether to give 85 mg (40%) of awhite solid: ¹HNMR (CD₃OD) δ 7.95-6.61 (m, 9H), 3.41-3.26 (m, 8H),3.20-3.07 (m, 2H), 2.47 (s, 3H), 1.42 (t, J=7 Hz, 3H); MS (ESI) 384.0(M+H)⁺; Purity (HPLC) >95%.

EXAMPLE 38

[0180] 4-(1-Piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole (Scheme1)

[0181] The title compound was prepared from4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and piperazine accordingto Method 1 to give 25 mg (12%) of a white solid: ¹HNMR (CD₃OD) δ7.91-6.79 (m, 9H), 3.49-3.30 (m, 8H), 2.48 (s, 3H); MS (ESI) 356.1(M+H)⁺; Purity (HPLC) >95%.

EXAMPLE 39

[0182] 4-(5-Aza-indolizidinyl)-1-(2-methylbenzenesulfonyl)-1H-indole(Scheme 1)

[0183] The title compound was prepared from4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and 5-aza-indolizidinylaccording to Method 1 to give 30 mg (13%) of a white solid: ¹H NMR onfree base (CDCl₃) δ 7.85-7.66 (m, 9H), 3.63-3.47 (m, 1H), 3.16-2.93 (m,3H), 2.67-2.45 (m, 5H), 2.51 (s, 3H), 2.33-2.19 (m, 2H), 1.92-1.74 (m,4H), 1.52-1.44 (m, 1H); MS (ESI) 396.0 (M+H)⁺; Purity (HPLC) >95%.

EXAMPLE 40

[0184]4-(4-Methyl-1-homopiperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole(scheme 1)

[0185] The compounds was prepared from4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and4-methyl-1-homopiperazine according Method 1 to give 20 mg (13%) of awhite solid: ¹H NMR (CD₃OD) δ 7.91-6.73 (m, 9H), 3.74-3.45 (m, 8H), 3.00(s, 3H), 2.47 (s, 3H), 2.34-2.26 (m, 2H); MS (ESI) 384.0 (M+H)⁺; Purity(HPLC) >95%.

EXAMPLE 41

[0186] 4-(3-Methyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole(Scheme 1)

[0187] The compound was prepared from4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and 3-methylpiperazineaccording to Method 1 to give 110 mg (38%) of a white solid: ¹HNMR(CD₃OD) δ 7.92-6.82 (m, 9H), 3.64-3.39 (m, 5H), 3.12-3.03 (m, 1H),2.92-2.83 (m, 1H), 2.47 (s, 3H), 1.40 (d, J=7 Hz, 3H); MS (ESI) 370.0(M+H)⁺; Purity (HPLC) 94%.

EXAMPLE 42

[0188]4-(cis-3,5-Dimethyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole(Scheme 1)

[0189] The compound was prepared according from4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole andcis-3,5-dimethyl-1-piperazine according to Method 1 to give 10 mg (4%)of a white solid: ¹HNMR (CD₃OD) δ 7.90-6.82 (m, 9H), 3.69-3.58 (m, 4H),2.83-2.74 (m, 2H), 2.45 (s, 3H), 1.41 (d, J=7 Hz, 6H); MS (ESI) 492.1(M+H)⁺; Purity (HPLC) 95%.

EXAMPLE 43

[0190]4-(4-Isopropyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole(Scheme 1)

[0191] The compound was prepared from4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and4-isopropyl-1-piperazine according to Method 1 to give 75 mg (56%) of awhite solid: ¹H NMR (CD₃OD) δ 7.92-6.81 (m, 9H), 3.75-3.56 (m, 5H),3.48-3.40 (m, 2H), 3.19-3.09 (m, 1H), 2.47 (s, 31H), 1.44 (d, J=7 Hz,6H); MS (ESI) 398.1 (M+H)⁺; Purity (HPLC) >95%.

EXAMPLE 44

[0192]4-((1S,4S)-2-Methyl-2,5-diazabicyclo[2.2.1]heptyl)-1-(2-methylbenzenesulfonyl)-1H-indole(Scheme 1)

[0193] The compound was prepared from4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and(1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane according to Method 1 togive 25 mg (19%) of a white solid: ¹H NMR (CD₃OD) δ 7.91-6.44 (m, 9H),4.67-4.63 (m, 1H), 4.35-4.33 (m, 1H), 4.09-4.07 (m, 1H), 3.99-3.95 (m,1H), 3.72-3.70 (m, 1H), 3.21-3.17 (m, 1H), 2.95 (s, 3H), 2.33-2.31 (m,2H); MS (ESI) 382.1 (M+H)⁺; Purity (HPLC) >95%.

EXAMPLE 45

[0194] 4-(4-Methyl-1-homopiperazinyl)-1-(benzenesulfonyl)-1H-indole(Scheme 1)

[0195] The compound was prepared from4-bromo-1-(benzenesulfonyl)-1H-indole and 4-methyl-1-homopiperazineaccording to Method 1 to give 4 mg (2%) of a white solid: ¹H NMR forfree base (CDCl₃) δ 7.86-7.11 (m, 8H), 6.71 (d, J=4 Hz, 1H) 6.54 (d, J=8Hz, 1H), 3.60-3.57 (m, 2H), 3.52-3.48 (m, 2H), 2.81-2.78 (m, 2H),2.68-2.64 (m, 2H), 2.39 (s, 3H), 2.04-2.00 (m, 2H); MS (ESI) 370.1(M+H)⁺; Purity (HPLC) >95%.

EXAMPLE 46

[0196] 4-(cis 3,5-Dimethyl-1-piperazinyl)-1-(benzenesulfonyl)-1H-indole(Scheme 1)

[0197] The title compound was prepared from4-bromo-1-(benzenesulfonyl)-1H-indole and cis 3,5-dimethyl-1-piperazineaccording to Method 1 to give 138 mg (52%) of a white solid: ¹HNMR(CD₃OD) δ 7.93-6.82 (m, 10H), 3.64-3.59 (m, 4H), 2.77-2.68 (m, 2H), 1.36(d, J=6 Hz, 6H); MS (ESI) 370.0 (M+H)⁺; Purity (HPLC) >95%.

EXAMPLE 47

[0198] 4-(4-Ethyl-1-piperazinyl)-1-(benzenesulfonyl)-1H-indole (Scheme1)

[0199] The title compound was prepared from4-bromo-1-(benzenesulfonyl)-1H-indole and 4-ethylpiperazine according toMethod 1 to afford 129 mg (48%) of a white solid: ¹H NMR (CD₃OD) δ7.94-6.81 (m, 10H), 3.69-3.62 (m, 4H), 2.34-3.26 (partly hidden) (m,4H), 3.14-3.04 (m, 2H), 1.40 (t, J=7 Hz, 3H); MS (ESI) 370.1 (M+H)⁺;Purity (HPLC) >95%.

EXAMPLE 48

[0200] 4-Piperazinyl-1-(4-nitro-benzenesulfonyl)-1H-indole (Scheme 1)

[0201] The title compound was prepared according to Method 5 from4-nitrobenzenesulfonyl chloride and the sodium salt of4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stock solution A) to give60.3 mg (86%) as HCl salt: ¹HNMR (CD₃OD) δ 8.34 (d, 2H, J=9.0 Hz), 8.18(d, 2H, J=9.0 Hz), 7.76-7.69 (m, 2H), 7.33-7.27 (m, 1H), 6.90-6.85 (m,2H) 3.44-3.30 (m, 8H, partly obscured); MS (ESI) 386.9 (M+H)⁺; Purity(HPLC) 95%.

EXAMPLE 49

[0202] 4-Piperazinyl-1-(4-bromo-benzenesulfonyl)-1H-indole (Scheme 1)

[0203] The title compound was prepared according to Method 5 from4-bromobenzenesulfonyl chloride and the sodium salt of4-(4-t-butyloxycarbonyl)-piperazinylindole (stock solution A) to give40.3 mg (53%) as HCl salt; ¹HNMR (CD₃OD) δ 7.81-7.61 (m, 6H), 7.30-7.24(m, 1H), 6.86-6.83 (m, 2H) 3.44-3.30 (m, 8H); MS (ESI) 419.9, 421.9(M+H)⁺; Purity (HPLC) 98%.

EXAMPLE 50

[0204] 4-Piperazinyl-1-(4-chloro-benzenesulfonyl)-1H-indole (Scheme 1)

[0205] The title compound was prepared according to Method 5 from4-chloro-benzenesulfonyl chloride and the sodium salt of4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stock solution A) to give42 mg (61%) as HCl salt: ¹HNMR (CD₃OD) δ 7.88 (d, 2H, J=8.7 Hz),7.72-7.63 (m, 2H), 7.50 (d, 2H, J=8.7 Hz), 7.30-7.24 (m, 1H), 6.86-6.84(m, 2H) 3.44-3.31 (m, 8H); MS (ESI) 375.9, 377.9 (M+H)⁺; Purity (HPLC)95%.

EXAMPLE 51

[0206] 4-Piperazinyl-1-(E 2-phenyl-ethensulfonyl)-1H-indole (Scheme 1)

[0207] The title compound was prepared according to Method 5 from 1-(E2-phenyl-ethensulfonyl chloride and the sodium salt of4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stock solution A) to give 8mg (11%) as HCl salt: ¹HNMR (CD₃OD) δ 7.78 (d, 1H, J=15.4 Hz) 7.68-7.25(m, 9H), 7.16 (d, 1H, J=15.4), 6.88-6.84 (m, 2H) 3.46-3.34 (m, 8 H); MS(ESI) 368.0 (M+H)⁺; Purity (HPLC) 97%.

EXAMPLE 52

[0208] 4-Piperazinyl-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indole(Scheme 1)

[0209] The title compound was prepared according to Method 5 from3-trifluoromethyl-benzenesulfonyl chloride and the sodium salt of4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stock solution A) to give42 mg (61%) of a white solid: ¹HNMR (CD₃OD) δ 8.21-8.16 (m, 2H)7.96-7.93 (m, 1H), 7.34-7.27 (m, 1H), 6.89-6.85 (m, 2H) 3.44-3.32 (m,8H); MS (ESI) 410.0 (M+H)⁺; Purity (HPLC) 95%.

EXAMPLE 53

[0210] 4-Piperazinyl-1-(4-cyanobenzenesulfonyl)-1H-indole (Scheme 1)

[0211] The title compound was prepared according to Method 5 from4-cyanobenzenesulfonyl chloride and the sodium salt of4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stock solution A) to give28 mg (42%) of a white solid: MS (ESI) 367.0 (M+H)⁺; Purity (HPLC) 95%.

EXAMPLE 54

[0212] 4-Piperazinyl-1-(4-chloro-7-chloro-2,1,3-benzoxadiazolesulfonyl)-1H-indole (Scheme 1)

[0213] The title compound was prepared according to Method 5 from4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole sulfonylchloride and thesodium salt of 4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stocksolution A) to give 12 mg (16%) of a white solid: ¹HNMR (CD₃OD) δ 8.42(d, 2H, J=7.1 Hz), 7.84-7.63 (m, 3H), 7.27-7.21 (m, 1H), 6.85-6.81 (m,2H) 3.43-3.27 (m, 8H, partly hidden); MS (EST) 418.0 (M+H)⁺; Purity(HPLC) 91%.

EXAMPLE 55

[0214] 4-Piperazinyl-1-(3-cyanobenzenesulfonyl)-1H-indole (Scheme 1)

[0215] The title compound was prepared according to Method 5 from4-trifluoromethyl-benzenesulfonyl chloride and sodium salt of4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stock solution A) to give68 mg (50%) of a white solid: MS (ESI) 367.1 (M+H)⁺; Purity (HPLC) 93%.

EXAMPLE 56

[0216] 4-Piperazinyl-1-(4-phenoxybenzenesulfonyl)-1H-indole (Scheme 1)

[0217] The title compound was prepared according to Method 5 from4-phenoxybenzenesulfonyl chloride and sodium salt of4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stock solution A) to give68 mg (87%) of a white solid: ¹HNMR (CD₃OD) 7.82-7.59 (m, 4H), 7.76-7.34(m, 4H), 6.88-6.78 (m, 6H) 3.45-3.30 (m, 8H); MS (ESI) 434.1 (M+H)⁺;Purity (HPLC) 95%.

EXAMPLE 57

[0218] 4-Piperazinyl-1-(4-chlorophenylmethanesulfonyl)-1H-indole (Scheme1)

[0219] The title compound was prepared according to Method 5 from4-chlorophenylmethanesulfonyl chloride and sodium salt of4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stock solution A) to give 3mg (4%) of a white solid: ¹H NMR (CD₃OD) δ 7.44 (d, 1 H. J=8.2 Hz)7.24-7.18 (m, 4H), 6.87-6.84 (m, 3H), 6.69-6.67 (m, 1H) 4.72 (s, 2H)3.43-3.31 (m, 8H, partly hidden); MS (ESI) 390.0, 392.1 (M+H)⁺; Purity(HPLC) 91%.

EXAMPLE 58

[0220] 4-Piperazinyl-1-(4-methylphenylmethanesulfonyl)-1H-indole (Scheme1)

[0221] The title compound was prepared according to Method 5 from4-methylphenylmethanesulfonyl chloride and sodium salt of4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stock solution A) to give 9mg (13%) of a white solid: ¹HNMR (CD₃OD) δ 7.46 (d, 1H, J=8.4 Hz)7.24-7.18 (m, 1H), 7.06 (d, 1H, J=4.0 Hz) 6.95-6.85 (m, 3H), 6.76-6.64(m, 3H) 4.65 (s, 2H) 3.47-3.35 (m, 8H) 2.24 (s, 3H); MS (ESI) 370.1(M+H)⁺; Purity (HPLC) 95%.

EXAMPLE 59

[0222] 4-Piperazinyl-1-(1,1-diphenylethanesulfonyl)-1H-indole (Scheme 1)

[0223] The title compound was prepared according to Method 5 from1,1-diphenylethanesulfonyl chloride and the sodium salt of4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stock solution A) to give57 mg (71%) of a white solid: ¹H NMR (CD₃OD) δ 7.59 (d, 1H, J=8.4 Hz),7.31-7.25 (m, 1H), 7.12-7.05 (m, 10H), 6.86-6.83 (m, 1H) 6.50-6.48 (m,1H) 6.42 (t, 1H, J=6.6 Hz) 4.28 (d, 2H, J 6.6 Hz) 3.47-3.32 (m, 8H); MS(ESI) 446.1 (M+H)⁺; Purity (HPLC) 92%.

EXAMPLE 60

[0224] 4-Piperazinyl-1-(4-trifluoromethoxybenzenesulfonyl)-1H-indole(Scheme 1)

[0225] The title compound was prepared according to Method 5 from4-trifluoromethoxybenzenesulfonyl chloride and the sodium salt of4-(4-t-butyloxycarbonyt)-piperazinyl-indole (stock solution A) to give46 mg (60%) of a white solid: ¹HNMR (CD₃OD) δ 8.07-8.04 (m, 2H),7.75-7.72 (m, 1H) 7.67-7.68 (m, 1H) 7.43-7.40 (m, 2H), 7.32-7.20 (m, 1H)6.87-6.85 (m, 2H) 3.44-3.31 (m, 8H, partly hidden); MS (ESI) 426.1(M+H)⁺; Purity (HPLC) 93%.

EXAMPLE 61

[0226]4-Piperazinyl-1-(5-[(benzoylamino)methyl]thiophene-2-sulfonyl)-1H-indole(Scheme 1)

[0227] The title compound was prepared according to Method 5 from5-[(benzoylamino)methyl]thiophene-2-sulfonylchloride and the sodium saltof 4-(4-t-butyloxycarbonyl)-piperazinyl-indole (stock solution A) togive 5 mg (6%) of a white solid: ¹H NMR (CD₃OD) δ 7.79-7.42 (m, 8H),7.30-7.24 (m, 1H) 7.00-6.98 (m, 1H) 6.85-6.81 (m, 2H) 3.39-3.28 (m, 8H,partly hidden); MS (ESI) 481.1 (M+H)⁺; Purity (HPLC) 91%.

EXAMPLE 62

[0228]1-[(N-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1-piperazinyl)-1H-indoleHydrochloride

[0229] The compound was prepared from 4-(4-boc-piperazinyl)-indole1-methyl-1H-imidazol-4-yl)sulfonyl chloride according to Method 3:Yield:74%. ¹H NMR (270 MHz, DMSO-d₆) δ 9.23 (br, 1H), 8.25 (s, 1H), 7.75 (s,1H), 7.61 (d, J=3 Hz, 1H), 7.53 (d, J=8 Hz, 1 H), 7.22 (t, J=8 Hz, 1H),6.86 (d, J=3 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 3.65 (s, 3H), 3.27 (m, 8H);MS (ESI+) for m/z 346 (M+H)⁺.

TABLE II Compounds prepared according to synthetic scheme 3.

EXAMPLE —SO₂—Ar R⁵ (68)5-(4-methyl-1-piperazinyl)-1-(phenylsulfonyl)-1H-indole

(69) 1-[(4-methylphenyl)sulfonyl]-5-(4-methyl-1-piperazinyl)-1H-indole

(70) 5-(4-isopropyl-1-piperazinyl)-1-(phenylsulfonyl)-1H-indole

(71) 5-(4-isopropyl-1-piperazinyl)-1-[(4-methylphenyl)sulfonyl]-1H-indole

(72) 1-[(3,4-dimethoxyphenyl)sulfonyly]5-(4-propyl-1-piperazinyl)-1H-indole

(73) 1-[(3-fluorophenyl)sulfonyl]-5-(4-propyl-1-piperazinyl)-1H-indole

(74) 5-(4-methyl-1-piperazinyl)-1-[(4-propylphenyl)sulfonyl]-1H-indole

(75) 5-(4-methyl-1-piperazinyl)-1-(1-naphthylsulfonyl)-1H-indole

(76) 1-([1,1′-biphenyl]-4-ylsulfonyl)-5-(4-methyl-1-piperazinyl)-1H-indole

(77) 1-[(4-methoxyphenyl)sulfonyl]-5-(4-methyl-1-piperazinyl)-1H- indole

(78) 1-[(3,4-dimethoxyphenyl)sulfonyl]-5-(4-methyl-1-piperazinyl)-1H-indole

(79) 1-[(2,4-difluorophenyl)sulfonyl]-5-(4-methyl-1-piperazinyl)-1H-indole

(80) N-(4-Methoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride

(81) N-(2,4-Difluorobenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride BVT.1311

(82) N-(4-Butoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride

(83) N-(3,4-Dimethoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole, hydrochloride

(84) N-(Biphenyl-4-sulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride

(85) N-(Napthalene-2-sulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride

(86) N-(4-Propylbenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride

(87) N-(3-Fluorobenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride

(88) N-(4-Methoxybenzenesulfonyl)-5-(piperazin-1-yl)-indole,hydrochloride

(89) N-(2,4-Difluorobenzenesulfonyl)-5-(piperazin-1-yl)-indole,hydrochloride

(90) N-(4-Butoxybenzenesulfonyl)-5-(piperazin-1-yl)-indole,hydrochloride

(91) N-(3,4-Dimethoxybenzenesulfonyl)-5-(piperazin-1-yl)-indole,dihydrochloride

(92) N-(Biphenyl-4-sulfonyl)-5-(piperazin-1-yl)-indole, dihydrochloride

(93) N-(Napthalene-2-sulfonyl)-5-(piperazin-1-yl)-indole,dihydrochloride

(94) N-(4-Propylbenzenesulfonyl)-5-(piperazin-1-yl)-indole,dihydrochloride

(95) N-(3-Fluorobenzenesulfonyl)-5-(piperazin-1-yl)-indole,dihydrochloride

(96) N-Benzenesulfonyl-5-(piperazin-1-yl)-indole, dihydrochloride1-(phenylsulfonyl)-5-(1-piperazinyl)-1H-indole

EXAMPLE 63 Intermediate

[0230] 5-Bromo-1-triisopropylsilyl-indole

[0231] 5-Bromoindole (3.92 g; 20 mmol) was dissolved in DCM (100 mL) andDMF (1 mL). NaH (0.88 g, 22 mmol; 60% in oil) was added to the cooledsolution. After stirring for 15 minutes, triisopropylsilyl chloride(3.86 g, 20 mmol) was added dropwise to the reaction mixture. After 3 h,water (1 mL) was added, followed by MgSO₄. The mixture was filtered andconcentrated and the residue put through a silica column with hexane aseluent. The product was obtained as a pale yellow oil (5.96 g, 17 mmol;yield 85%). ¹H NMR (CDCl₃) δ 1.13 (18H, d, J=8), 1.67 (3H, m), 6.55 (1H,d, J=3), 7.21 (1H, dd, J=9, 2), 7.24 (1H, d, J=3), 7.36 (1H, d, J=9) and7.74 (1H, d, J=2).

EXAMPLE 64 Intermediate

[0232] 5-(4-Methylpiperazin-1-yl)-indole

[0233] 5-Bromo-1-triisopropylsilyl-indole (5.8 g, 16.4 mmol),N-methylpiperazine (1.8 g, 18 numol), NaOt-Bu (2.2 g, 23 mmol), Pd(OAc)₂(37 mg, 0.16 mmol), Pt-Bu₃ (66 mg, 0.33 nmmol) and xylene (30 mL) weremixed and heated to 130° C. under stirring for 5 h. The crude materialwas chromatographed on a silica column using DCM/MeOH 95/5 as eluent.Concentration of the main fractions left 5.6 g of an oil which wasdissolved in MeCN (10 mL), 20 mL of a 1 M solution of tetrabutylammoniumfluoride in THF was added and the mixture left over-night. The reactionmixture was put on a silica column and eluted with DCM/MeOH 95/5 to givethe product as an oil (2 g, 9.3 mmol; yield 57 %) ¹H NMR (CDCl₃) δ 2.37(3H, s), 2.64 (4H, t, J=5), 3.19 (4H, t, J=5), 6.44-6.48 (1 H, m),6.95-7.00 (1H, m), 7.16 (1H, d, J=3), 7.18 (1H, d, J=2), 7.29 (1H, d,J=9) and 8.12 (1H, bs).

[0234] Intermediates 65-67 were prepared using the same method as forintermediate 64.

EXAMPLE 65 Intermediate

[0235] 5-(4-Isopropylpiperazin-1-yl)-indole (0.46 g, 1.9 mmol; yield63%), ¹H NMR (CDCl₃) δ 1.12 (6H, d, J=7), 2.70-2.78 (5 H, m), 3.15-3.22(4H, m), 6.45-6.49 (1H, m), 6.97-7.01 (1H, dm), 7.14-7.19 (2H, m), 7.30(1H, d, J=9) and 8.05 (1H, bs).

EXAMPLE 66 Intermediate

[0236] 5-(4-Benzylpiperazin-1-yl)-indole

[0237] (3.6 g, 12.4 mmol; yield 55%), ¹H NMR (CDCl₃) δ 2.67 (4H, t,J=5), 3.18 (4H, t, J=5), 3.60 (2H, s), 6.44-6.47 (1H, m), 6.97 (2H, dd,J=9,3),7.13-7.17 (2H, m), 7.25-7.39 (5 H, m) and 8.01 (1H, bs).

EXAMPLE 67 Intermediate

[0238] 5-(4-Propylpiperazin-1-yl)-indole

[0239] (0.54 g, 2.2 mmol; yield 24%), ¹H NMR (CDCl₃) 8 0.94 (3H, t,J=7), 1.53-1.62 (2 H, m), 2.37-2.43 (2H, m), 2.65-2.73 (4H, m),3.17-3.22 (4H, m), 6.45-6.48 (I H, m), 6.96-7.00 (1H, dm), 7.14-7.19(2H, m), 7.30 (1H, d, J=9) and 8.13 (1H, bs).

EXAMPLE 68

[0240] N-Benzenesulfonyl-5-(4-methylpiperazin-1-yl)-indole

[0241] 5-(4-Methylpiperazin-1-yl)-indole (215 mg, 1 mmol),benzenesulfonylchloride (265 mg, 1.5 mmol) and Aliquat 336 (10 mg) weredissolved in DCM (10 mL). Aqueous NaOH (20%, 2 mL) was added and themixture was stirred vigorously for 6 h. The organic layer was separated,dried and concentrated to give the crude as an oil that was purified ona silica column using DCM and MeOH as eluent. The pure fractions wereconcentrated to give an oil (260 mg, 0.66 inmol) ¹H NMR (CDCl₃) δ 2.35(3H, s), 2.59 (4H, t, J=5), 3.18 (4H, t, J=5), 6.57 (1H, d, J=4),6.98-7.03 (2H, m), 7.38-7.54 (4H, m), 7.82-7.90 (3 H, m); MS (posES-FIA)355.1345 M⁺; Purity (HPLC chromsil C18) >98%.

[0242] Examples 69-87 were prepared using the same method as forExample 1. Examples 72-87 are reported as hydrochloride salts.

EXAMPLE 69

[0243] N-(4-Methylbenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole(0.24 g, yield 59%) ¹H NMR (CDCl₃) δ 2.33 (3H, s), 2.37 (3H, s), 2.61(4H, t, J=5), 3.18 (4H, t, J=5), 6.55 (1H, d, J=3), 6.98-7.30 (2H, m),7.19 (2H, d, 7.47 (1H, d, J=4), 7.72 (2H, d, J=9) and 7.86 (1H, d, J=9);MS (posES-FIA) 369.1502 M⁺; Purity (HPLC chromsil C18) >98%.

EXAMPLE 70

[0244] N-Benzenesulfonyl-5-(4-isopropylpiperazin-1-yl)-indole

[0245] (0.24 g, yield 57%), ¹H NMR (CDCl₃) δ 1.12 (6H, d, J=7),2.68-2.77 (5H, m), 3.15-3.25 (4H, m), 6.57 (1H, d, J=5), 6.98-7.04 (2H,m), 7.39-7.44 (2H, m), 7.46-7.54 (1 H, m) and 7.81-7.89 (3H, m); MS(posES-FIA) 383.1655 M⁺; Purity (HPLC chromsil C18) >98%.

EXAMPLE 71

[0246] N-(4-Methylbenzenesulfonyl)-5-(4-isopropylpiperazin-1-yl)-indole

[0247] (0.29 g, yield 67%), ¹H NMR (CDCl₃) δ 1.11 (6H, d, J=6), 2.33(3H, s), 2.67-2.78 (5H, nm), 3.15-3.25 (4H, m), 6.54 (1H, d, J=4),6.97-7.03 (2H, m), 7.19 (2H, d, J=8), 7.46 (1H, d, J=4), 7.67-7.81 (3H,m) and 7.86 (1H, d, J=9); MS (posES-FIA) 397.1823 M⁺; Purity (HPLCchromsil C1 8) >90%.

EXAMPLE 72

[0248]N-(3,4-Dimethoxybenzenesulfonyl)-5-(4-propylpiperazin-1-yl)-indole,Hydrochloride

[0249] (0.27 g, yield 67%), ¹H NMR (CDCl₃) δ 1.10 (3H, t, J=7),1.93-2.03 (2H, m), 3.10-3.20 (2H, m), 3.63-3.70 (4H, m), 3.88 (3H, s),3.90 (3H, s), 4.30-4.42 (2H, m), 4.82-4.94 (2H, m), 6.76 (1H, d, J=4),6.87-6.94 (2H, m), 7.53-7.60 (2H, m), 7.72-7.76 (1H, m), 7.83-7.88 (1H,m), 8.08-8.12 (1H, m), 8.16-8.20 (1H, m) and 13.45 (1H, bs); MS(posES-FIA) 443.1871 M⁺; Purity (HPLC chromsil C18) >75%.

EXAMPLE 73

[0250] N-(3-Fluorobenzenesulfonyl)-5-(4-propylpiperazin-1-yl)-indole,Hydrochloride

[0251] (0.16 g, yield 67%), ¹H NMR (MeOH d6) δ 1.02 (3H, t, J=7),1.72-1.84 (2H, m), 3.02-3.18 (4H, m), 3.19-3.26 (2H, m), 3.60-3.68 (2H,m), 3.71-3.80 (2H, m), 6.67 (1 H. d, J=4), 7.08-7.13 (1H, m), 7.15-7.18(1H, m), 7.30-7.37 (1H, m), 7.46-7.54 (1H, m), 7.58-7.64 (2H, m),7.66-7.72 (1H, m) and 7.86-7.91 (1H, m); MS (posES-FIA) 401.1585 M⁺;Purity (HPLC chromsil C18) >90%.

EXAMPLE 74

[0252] N-(4-Propylbenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole,Hydrochloride (0.15 g, yield 38%) ¹H NMR (CDCl₃) δ 0.90 (3H, t, J=7),1.56-1.66 (2H, m), 2.60 (2 H, t, J=8), 2.98 (3H, s), 3.56-3.68 (4H, m),4.27-4.40 (2H, m), 4.64-4.74 (2H, m), 6.74 (1 H, d, J=3),7.25-7.29 (2H,m), 7.71-7.81 (4H, m), 8.06-8.13 (2H, m) and 13.89 (1 H, bs); MSposES-FIA) 397.1813 M⁺; Purity (HPLC chromsil C18) >93%.

EXAMPLE 75

[0253] N-(1-Naphtalenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole,Hydrochloride (0.18 g, yield 45%) ¹H NMR (CDCl₃) δ 2.97 (3H, s), 3.59(4H, t, J=15), 4.35-4.46 (2 H, m), 4.68-4.78 (2H, m), 6.75 (1H, d, J=3),7.50-7.76 (4H, m), 7.88-7.98 (3H, m), 8.11-8.15 (2H, m), 8.34-8.38 (1H,m), 8.62 (1H, d, J=9) and 13.94 (1H, bs); MS (posES-FIA) 405.1503 M⁺;Purity (HPLC chromsil C 18) >90%.

EXAMPLE 76

[0254] N-(Biphenyl-4-sulfonyl)-5-(4-methylpiperazin-1-yl)-indole,Hydrochloride

[0255] (0.13 g, yield 30%) ¹H NMR (MeOH-d₆) δ 2.93 (3H, s), 3.05-3.15(2H, m), 3.20-3.30 (2H, m), 3.50-3.60 (2H, m), 3.70-3.80 (2H, m), 6.66(1H, d, J=5),7.11 (1H, dd, J=9, 3), 7.16 (1H, d, J=3), 7.32-7.43 (3H,m), 7.51-7.56 (2H, m), 7.61 (1H, d, J=4), 7.66-7.70 (2H, m) and7.88-7.94 (3H, m); MS posES-FIA) 431.1662 M⁺; Purity (HPLC chromsil C18)>98%.

EXAMPLE 77

[0256] N-(4-Methoxybenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole,Hydrochloride

[0257] (0.17 g, yield 44%) ¹H NMR (CDCl₃) δ 2.98 (3H, s), 3.55-3.68 (4H,m), 3.82 (3H, s), 4.30-4.45 (2H, m), 4.66-4.76 (2H, m), 6.72 (1H, d,J=4), 6.93 (2H, d, J=9), 7.71 (1 H, d, J=4), 7.74-7.79 (1H, m), 7.83(2H, d, J=9), 8.10 (2H, d, J=9) and 13.97 (1H, bs); MS (posES-FIA)385.1456 M⁺; Purity (HPLC chromsil C18) >95%.

EXAMPLE 78

[0258]N-(3,4-Dimethoxybenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole,Hydrochloride

[0259] (0.13 g, yield 28%) ¹H NMR (CDCl₃) δ 2.98 (3H, s), 3.55-3.70 (4H,m), 3.88 (3H, s), 3.89 (3H, s), 4.32-4.45 (2H, m), 4.66-4.78 (2H, m),6.75 (1 H. d, J=4), 6.85-6.93 (2 H, m), 7.53-7.58 (1H, m), 7.73 (1H, d,J=4), 7.77-7.82 (1H, m), 8.08-8.14 (2H, m) and 13.97 (1H, bs); MS(posES-FIA) 415.1561 M⁺; Purity (HPLC chromsil C18) >80%.

EXAMPLE 79

[0260]N-(2,4-Difluorobenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole,Hydrochloride

[0261] (0.23 g, yield 53%) ¹H NMR (CDCl₃) δ 2.2.99 (3H, s), 3.55-3.68(4H, m), 4.35-4.45 (2 H, m), 4.71-4.82 (2H, m), 6.77 (1H, d, J=4),6.84-6.93 (2H, m), 7.04-7.12 (1H, m), 7.75-7.82 (2H, m), 7.98 (1H, d,J=9), 8.10-8.20 (2H, m) and 13.88 (1H, bs); MS (posES-FIA) 391.1155 M⁺;Purity (HPLC chromsil C18) >88%.

EXAMPLE 80

[0262] N-(4-Methoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,Hydrochloride

[0263] (0.34 g, yield 61%). ¹H NMR (CD₃OD) δ 3.26-3.29 (8H, m), 3.76(3H, s), 4.40 (2H, s), 6.93 (1H, d, J=9), 7.08 (1H, dd, J=9, 3), 7.17(1H, d, J=3), 7.46-7.51 (3H, m), 7.52-7.57 (3H, m), 7.76 (2H, d, J=9)and 7.86 (1H, d, J=9); MS (posES-FIA) 461.1763 M⁺; Purity (HPLC chromsilC1 8) >90%.

EXAMPLE 81

[0264]N-(2,4-Difluorobenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,Hydrochloride

[0265] (0.30 g, yield 64%). 1H NMR (CD₃OD) δ 3.30-3.80 (8H, m), 4.40(2H, s), 6.66 (1H, d, J=4), 7.04-7.15 (3H, m), 7.30 (1H, d, J=3),7.43-7.47 (3H, m), 7.52-7.56 (2H, m), 7.57-7.66 (1H, m), 7.74 (1H, d,J=9) and 8.06-8.14 (1H, m); MS (posES-FIA) 467.1492 M⁺; Purity (HPLCchromsil C18) >98%.

EXAMPLE 82

[0266] N-(4-Butoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,Hydrochloride

[0267] (0.30 g, yield 64%). ¹H NMR (DMSO d₆) δ 0.86 (3H, t, J=7),1.29-1.42 (2H, m), 1.55-1.69 (2H, m), 3.05-3.37 (6H, m), 3.60-3.70 (2H,m), 3.97 (2H, t, J=6), 4.35 (2H, s), 6.70 (1H, d, J=3), 7.02-7.15 (4H,m), 7.43-7.50 (3H, m), 7.65-7.71 (3H, m), 7.78-7.86 (3H, m) and 11.45(1H, bs); MS (posES-FIA) 503.2236 M⁺; Purity (HPLC chromsil C18) >95%.

EXAMPLE 83

[0268]N-(3,4-Dimethoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,Hydrochloride

[0269] (0.36 g, yield 68%). ¹H NMR (DMSO d₆) δ 3.10-3.40 (6H, m),3.65-3.85 (2H, m), 3.76 (6H, s), 4.35 (2H, s), 6.70 (1H, d, J=4),7.04-7.14 (3H, m), 7.34 (1H, d, J=2), 7.42-7.47 (3H, m), 7.50 (1H, dd,J=9, 2), 7.65-7.70 (2H, m), 7.73 (1H, d, J=4), 7.83 (1H, d, J=9) and11.65 (1H, bs); MS (posES-FIA) 491.1875 M⁺; Purity (HPLC chromsil C18)>98%.

EXAMPLE 84

[0270] N-(Biphenyl-4-sulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,Hydrochloride

[0271] (0.35 g, yield 64%). ¹H NMR (DMSO d₆) δ 3.10-3.20 (4H, m),3.30-3.40 (2H, m), 3.70-3.80 (2H, m), 4.36 (2H, s), 6.74 (1H, d, J=4),7.05-7.13 (2H, m), 7.40-7.50 (6 H, m), 7.58-7.63 (2H, m), 7.63-7.68 (2H,m), 7.76 (1H, d, J=4), 7.82-7.87 (3H, m), 7.98 (2H, d, J=9) and 10.81(1H, bs); MS (posES-FIA) 507.1981 M⁺; Purity (HPLC chromsil C18) >98%.

EXAMPLE 85

[0272] N-(Napthalene-2-sulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,Hydrochloride

[0273] (0.40 g, yield 55%). ¹H NMR (DMSO d₆) δ 3.05-3.35 (6H, m), 3.66(2H, d, J=12), 4.33 (2H, s), 6.71 (1H, d, J=4), 6.99 (1H, dd, J=9, 2),7.10 (1H, d, J=4), 7.41-7.45 (3H, m), 7.58-7.75 (6H, m), 8.00 (1H, d,J=4), 8.07 (1H, d, J=8), 8.29 (1H, d, J=9), 8.32 (1H, d, J=7), 8.62 (1H,d, J=9) and 11.53 (1H, bs); MS posES-FIA) 481.1842 M⁺; Purity (HPLCchromsil C18) >98%.

EXAMPLE 86

[0274] N-(4-Propylbenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,Hydrochloride

[0275] (0.49 g, yield 63%). ¹H NMR (DMSO d₆) δ 0.81 (3H, t, J=7),1.44-1.56 (2H, m), 2.54 (2H, t, J=8), 3.10-3.27 (6H, m), 3.28-3.38 (2H,m), 4.35 (2H, s), 6.70 (1H, d, J=4), 7.05-7.09 (1H, m), 7.10-7.12 (1H,m), 7.37 (2H, d, J=8), 7.43-7.48 (3H, m), 7.63-7.67 (2H, m), 7.69 (1H,d, J-4), 7.77-7.84 (3H, m), and 11.37 (1H, bs); MS (posES-FIA) 473.2152M⁺; Purity (HPLC chromsil C18) >98%.

EXAMPLE 87

[0276] N-(3-Fluorobenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,Hydrochloride

[0277] (0.36 g, yield 70%). ¹H NMR (DMSO d₆) δ 3.10-3.23 (2H, m),3.26-3.40 (4H, m), 3.65-3.77(2H, m), 4.37(2H, s), 6.75 (1H, d, J=4),7.11(1H, dd, J-9, 2), 7.17(1H, d, J=2), 7.40-7.45 (3H, m), 7.48-7.56(1H, m), 7.58-7.65 (1H, m), 7.65-7.71 (2H, m), 7.73-7.78 (2H, m),7.80-7.86 (2H, m) and 11.79 (1H, bs); MS (posES-FIA) 449.1595 M⁺; Purity(HPLC chromsil C18) >98%.

EXAMPLE 88

[0278] N-(4-Methoxybenzenesulfonyl)-5-(piperazin-1-yl)-indole,Hydrochloride

[0279] N-(4-Methoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole(0.25 g, 0.54 mmol) was dissolved in DCM (4 mL), a-chloroethylchlorofonnate (0.150 g, 1.05 mmol) was added and the mixture left atroom temperature for 2 h after which it was concentrated. MeOH (10 mL)was added and the mixture refluxed for 2 hrs and then concentrated togive the product (0.22 g, quantitative yield). ¹H NMR (MeOH d₆) δ3.39-3.47 (8H, m), 3.77 (3H, s), 6.64 (1H, d, J=3), 6.94 (2H, d, J=9),7.15 (1H, dd, J=9, 2), 7.26 (1H, d, J=2), 7.59 (1H, d, J=4), 7.80 (2H,d, J=9) and 7.90 (1H, d, J=9); MS (posES-FIA) 371.1304 M⁺; Purity (HPLCchromsil C18) >98%. Examples 89-95 were prepared using the sameprocedure as in example 88.

EXAMPLE 89

[0280] N-(2,4-Difluorobenzenesulfonyl)-5-(piperazin-1-yl)-indole,Hydrochloride

[0281] (Isolated 0.20 g). ¹H NMR (CDCl₃) δ 3.49-3.54 (4H, m), 3.57-3.62(4H, m), 6.71 (1H, d, J=4), 7.04-7.15 (2H, m), 7.28 (1H, dd, J=9,3),7.51 (1H, d, J=3), 7.62-7.65 (1H, m), 7.81 (1H, d, J=9) and 8.08-8.16(1H, m); MS posES-FIA) 377.1012 M⁺; Purity (HPLC chromsil C18) >98%.

EXAMPLE 90

[0282] N-(4-Butoxybenzenesulfonyl)-5-(piperazin-1-yl)-indole,Hydrochloride

[0283] (Isolated 0.30 g) ¹H NMR (DMSO d₆) δ 0.84 (3H, t, J=8), 1.28-1.39(2H, m), 1.55-1.65 (2H, m), 3.22-3.30 (4H, m), 3.40-3.48 (4H, m), 3.95(2H, t, J=7), 6.73 (1H, d, J=4), 7.00 (2H, d, J=9), 7.19 (1H, d, J=9),7.29 (1H, bs), 7.71(1H, d, J=4), 7.84 (3H, d, J=9) and 9.64 (1H, bs); MS(posES-FIA) 413.1770 M⁺; Purity (HPLC chromsil C18) >88%.

EXAMPLE 91

[0284] N-(3,4-Dimethoxybenzenesulfonyl)-5-(piperazin-1-yl)-indole,Dihydrochloride

[0285] (Isolated 0.24 g ). ¹H NMR (DMSO d₆) δ 3.28-3.36 (4H, m),3.48-3.55 (4H, m), 3.75 (3 H, s), 3.76 (3H, s), 6.76 (1H, d, J=4), 7.05(1H, d, J=9), 7.23-7.44 (3H, m), 7.53 (1 H, dd, J=9, 3), 7.80 (1H, d,J=4), 7.93 (1H, d, J=9), and 9.81 (2H, bs); MS (posES-FIA) 401.1401 M⁺;Purity (HPLC chromsil C18) >98%.

EXAMPLE 92

[0286] N-(Biphenyl-4-sulfonyl)-5-(piperazin-1-yl)-indole,Dihydrochloride

[0287] (Isolated 0.21 g). ¹H NMR (DMSO d₆) δ 3.16-3.23 (4H, m),3.27.3.32 (4 H. m), 6.74 (1H, d, J=4), 7.07-7.14 (2H, m), 7.38-7.49 (3H,m), 7.63-7.68 (2H, m), 7.75 (1H, d, J=4), 7.82-7.87 (3H, m), 7.98 (2H,d, J=9) and 9.00 (2H, bs); MS (posES-FIA) 417.1519 M⁺; Purity (HPLCchromsil C18) >98%.

EXAMPLE 93

[0288] N-(Napthalene-2-sulfonyl)-5-(piperazin-1-yl)-indole,Dihydrochloride

[0289] (Isolated 0.25 g). ¹H NMR (DMSO d₆) δ 3.15-3.25 (4H, m),3.30-3.36 (4H, m), 6.73 (1 H, d, J=4), 7.05 (1H, dd, J=9, 3), 7.17 (1H,d, J=3), 7.61-7.74 (4H, m), 8.02 (1H, d, J=4), 8.07 (1H, d, J=8), 8.30(1H, d, J=8), 8.33 (1H, d, J=8), 8.62 (1H, d, J=9) and 9.46 (2H, bs); MS(posES-FIA) 391.1349 M⁺; Purity (HPLC chromsil C18) >98%.

EXAMPLE 94

[0290] N-(4-Propylbenzenesulfonyl)-5-(piperazin-1-yl)-indole,Dihydrochloride

[0291] (Isolated 0.24 g). ¹H NMR (DMSO d₆) δ 0.80 (3H, t, J=8),1.44-1.55 (2H, m), 2.53 (2H, t, J=8), 3.18-3.26 (4H, m), 3.36-3.42 (4H,m), 6.73 (1H, d, J=4), 7.14 (1H, dd, J=9, 2), 7.21 (1H, d, J=3), 7.36(2H, d, J=8), 7.71 (1H, d, J=4), 7.79-7.85 (3H, m), 9.52 (2 H, bs); MS(posES-FIA) 383.1679 M⁺; Purity (HPLC chromsil C18) >98%.

EXAMPLE 95

[0292] N-(3-Fluorobenzenesulfonyl)-5-(piperazin-1-yl)-indole,Dihydrochloride

[0293] (Isolated 0.18 g). ¹H NMR (DMSO d₆) δ 3.31-3.28 (4H, m),3.32-3.43 (4H, m), 6.77 (1 H, d, J=4), 7.14 (1H, dd, J=9, 3), 7.19 (1H,d, J=2), 7.50-7.58 (1H, m), 7.59-7.66 (1 H, m), 7.73-7.79 (2H, m),7.80-7.87 (1H, m) and 9.53 (2H, bs); MS (posES-FIA) 359.1109 M⁺, Purity(HPLC chromsil C18) >98%.

EXAMPLE 96

[0294] N-Benzenesulfonyl-5-(piperazin-1-yl)-indole, Dihydrochloride

[0295] 1-Benzenesulfonyl-5-bromo-indole (0.336 g, 1 mmol), piperazine(0.516 g, 6 mmol), CsCO₃ (0.456 g, 1.4 mmol), Pd₂(dba)₃ (46 mg, 0.05mmol), BINAP (62 mg, 0.1 mmol) and xylene (10 mL) were mixed and heatedto 120° C. under stirring for 18 h. The product was isolated as thehydrochloride salt (0.05 g). ¹H NMR (CDCl₃) δ 3.00-3.16 (8H, m), 6.57(1H, d, J=3), 6.99 (1H, s), 7.02 (1H, d, J=3), 7.40 (2H, t, J=8),7.47-7.53 (2H, m) and 7.81-7.90 (3H, m); MS (posES-FIA) 341.1187 M⁺;Purity (HPLC chromsil C18) >98%.

Exemple 98

[0296] Preparation of 3-substituted-1-arylsulfonyl indole,hydrochloride.

[0297] (i) p-Fluoro-sulfonylchloride, NaH, DMF.

EXAMPLE 97 Intermediate

[0298] 3-(1-azabicyclo[2.2.2]oct-2-en-3-yl)-1H-indole, Oxalate

[0299] The compound was obtained according to the procedure described inthe literature (Illi, V. O. Synthesis 1979, 136; Boettcher, H.;Seyfried, C.; Minck, K. O.; Wolf H. P. Ger. Offen. (1991), DE90-4009565). ¹H NMR (400 MHz, DMSO-d₆) δ 11.48 (s, 1H), 7.75-7.70 (m,2H), 7.42 (d, J=8 Hz, 1H), 7.20-7.05 (m, 2H), 6.92 (s, 1H), 3.34(s, 1H),3,26 (br, 2H), 2.84 (br, 2H), 1.88 (br, 2H), 1.63 (br, 2H).

EXAMPLE 98

[0300]3-(1-Azabicyclo[2.2.2]oct-2-en-3-yl)-1-[(4-fluorophenyl)sulfonyl]-1H-indole

[0301] At 0° C. 3-(3-indolyl)-2,3-dihydroquinuclidine (179 mg, 0.80mmol) was added to a suspension of NaH (20 mg, 0.85 mmol) in DMF (1 mL)and stirred for 15 min. Then the 4-fluorophenylsulfonyl chloride (174mg, 0.90 mmol) was added and the resulting solution was stirred for 30min at 0° C. and 3h at room temperature. The DMF was evaporated and theresulting solid was chromatographed (Eluant CH₂Cl₂ /MeOH, 90/10) toafford 100 mg (32%) of the desired compound. ¹H NMR (270 MHz, DMSO-d₆) δ8.25 -8.10 (m, 3H), 7.99 (d, J=8 Hz, 1H), 7.83 (d, J=8Hz, 1H), 7.65-7.30(m, 3H), 7.20-7.05 (m, 2H), 3,18 (br, 2H), 2.75 (br, 2H), 1.78 (br, 2H),1.50 (br, 2H); MS (ESI+) for m/z 383 (M+H)⁺.

EXAMPLE 99 Intermediate

[0302] tert-Butyl4-[2-iodo-1-(phenylsulfonyl)-1H-indol-4-yl]-1-piperazinecarboxylate

[0303] A mixture of butylmagnesium chloride (1 mL, Immol, 2.0 M inether) and di-isopropyl amine (0.279 mL, 2 mmol) in dry THF (5 mL) wasstirred for 4 h under inert atmosphere at room temperature. A solutionof tert-butyl4-[1-(phenylsulfonyl)-1H-indol-4-yl]-1-piperazinecarboxylate (220 mg,0.5 mmol) in THF (2 mL) was added slowly and the resulting mixturestirred for 2 h at room temperature. A solution of iodine (380 mg, 2.2mmol) in THF (2 mL) was added dropwise and the mixture was stirredovernight. After evaporation of the solvent in vacuo, the residue wastreated with an aqueous solution of NH₄Cl (10 mL). The mixture wasextracted with CH₂Cl₂ (3×10 mL) and the combined organic layers weredried (MgSO₄) and concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂) using CH₂Cl₂ as eluent to give 100 mg(35%).¹H NMR (500 MHz, CDCl₃) δ 8.05-7.80 (m, 3H), 7.60-7.35 (m, 3H),7.19 (t, J=8 Hz, 1 H), 6.98 (s, 1H), 6.72 (d, J=8 Hz, 1H), 3.62 (m, 4H),3.05 (m, 4H), 1.47 (in, 9H); MS (ESI+) for m/z 568 (M+H)⁺.

EXAMPLE 100

[0304] 2-Iodo-1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indoleHydrochloride

[0305] In CH₂Cl₂ (1 mL) tert-butyl4-[2-iodo-1-(phenylsulfonyl)-1H-indol-4-yl]-1-piperazinecarboxylate (25mg, 0.044 mmol) and HCl in ether (1 mL) were added and shaken for 2 h atroom temperature. The resulting precipitate was filtered off and washedwith ether giving 20 mg of the desired compound. ¹H NMR (270 MHz,DMSO-d₆) δ 9.02 (br, 1H), 7.90-7.80 (m, 3H), 7.75-7.55 (m, 3H), 7.32 (s,1H), 7.22 (t, J=8 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 3.35-310 (in, 8H); MS(ESI+) for m/z 468 (M+H)⁺.

EXAMPLE 101 Intermediate

[0306] tert-Butyl4-[2-phenyl-1-(phenylsulfonyl)-1H-indol-4-yl]-1-piperazinecarboxylate

[0307] tert-Butyl4-[2-iodo-1-(phenylsulfonyl)-1H-indol-4-yl]-1-piperazinecarboxylate(40mg, 0.07 mmol), phenyl boronic acid (12 mg, 0.1 mmol), Pd(PPh₃)₄ (2 mg,0.002 mmol) and a 2M aqueous solution of K₂CO₃ (0.075 mL) were stirredfor 3 days at 80° C. in dimethoxyethane (2 mL). After evaporation of thesolvent, the crude was purified by column chromatography (SiO2) and ledto 30 mg of the desired compound (80%). ¹H NMR (270 MHz, DMSO-d₆) δ 8.02(d, J=8 Hz, 1H), 7.55-7.20 (in, 11H), 6.78 (t, J=8 Hz, 1H), 7.57 (s,1H), 3.58 (in, 4H), 3.02 (in, 4H), 1.48 (in, 9H). MS (ESI+) for m/z 518(M+H)⁺.

EXAMPLE 102

[0308] 2-Phenyl-1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indoleHydrochloride

[0309] tert-Butyl4-[2-phenyl-1-(phenylsulfonyl)-1H-indol-4-yl]-1-piperazinecarboxylate(30 mg, 0.058 mmol) was dissolved in CH₂Cl₂ (1 mL) followed by additionof HCl in ether (1 mL). The reaction was shaken for 2 h at roomtemperature. The resulting precipitate was filtered off and washed withether giving 20 mg of the desired compound (80%). ¹H NMR (270 MHz,DMSO-d₆) δ 9.02 (br, 1H), 7.90-7.80 (m, 3H), 7.75-7.55 (m, 3H), 7.32 (s,1H), 7.22 (t, J=8 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 3.35-310 (m, 8H). MS(ESI+) for m/z 418 (M+H)⁺.

EXAMPLE 103 Intermediate

[0310]4-Trifluoromethanesulfonyloxy-2-methyl-1-tetrabutyldimethylsilylindole

[0311] 4-Hydroxy-2-methylindole (3.0 g, 20 mmol) was dissolved in 30 mLof DCM followed by addition of triethylamine (4.2 mL). Solution wascooled (ice bath) and a solution of trifluoromethanesulfonic anhydride(6.3 g, 22 nmmol) in DCM (6 mL) was slowly added under stirring. After10 minutes the solution was washed by aqueous K₂CO₃, dried (K₂CO₃) andsolvent was evaporated. Compound was dissolved in THF (10 mL) and NaH(0.8 g of 80% suspension in oil) was added. TBDMSCl (3.3 g, 22 mmol) inTHF (5 mL) was added. The solution was diluted by 20 mL of DCM, washedby aqueous NH₄Cl. Organic phase was dried and evaporated. The compoundwas purified by chromatography (SiO₂ hexane-ether). Yield 5.7 g (75%):¹H NMR (CDCl₃) δ 7.48 (d, J=7.9 Hz, 1H), 7.10-6.96 (m, 2H), 6.44 (s,1H), 2.50 (s, 3H), 0.96 (s, 9H), 0.64 (s, 6 H); MS (ESI) 381.1 (M+H).

EXAMPLE 104 Intermediate

[0312] 4-(N-Boc-piperazinyl)-2-methyl-1-tetrabutyldimethylsilylindole

[0313]4-trifluoromethanesulfonyloxy-2-methyl-1-tetrabutyldimethylsilylindole(1.0 g, 2.6 numol) and boc-piperazine (0.73 g, 3.9 mmol) were reactedaccording to Method 1 to give 0.75 g (67%) of a solid: ¹HNMR (CDCl₃) δ7.20 (d, J=8.2 Hz, 1H), 6.96 (t, 1H), 6.55 (d, J=7.4 Hz, 1H), 6.31 (s,1H), 3.63 (pt, 4H), 3.11 pt, 4H), 2.47 (s, 3H), 1.48 (s, 9 H), 0.94 (s,9H), 0.64 (s, 6H); MS (ESI) 417.4 (M+H).

EXAMPLE 105

[0314] 4-Piperazinyl-2-methyl-1-benzosulfonylindole trifluoroacetate

[0315] 4-(N-Boc-piperazinyl)-2-methyl-1-tetrabutyldimethylsilylindole(0.2 g, 0.48 mmol) was dissolved in ethyl acetate (5 ml) followed by theaddition of a solution of sodium fluoride (0.1 g) in water (1 mL).Mixture was vigorously stirred (50° C.) for 2 h. The organic phase wasseparated, dried and evaporated. The crude was dissolved in DCM (10 mL)followed by the addition of benzosulfonylchloride (0.1 g, 0.58 mmol) andaqueous NaOH (0.5 mL, 50% water solution). The mixture was vigorouslystirred for 1 h. Water (5 mL) was added, the organic phase wasseparated, dried and evaporated. The crude was dissolved in DCM (10 mL)and trifluoroacetic acid (1 mL) was added. After 3 h solvent wasevaporated and compound was crystallized from ethanol. Yield 60 mg(54%): ¹H NMR (CDCl₃) δ 7.83-7.77 (m, 3H), 7.59-7.56 (m, 1H), 7.50-7.46(m, 2H), 7.19 (t, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 3.41 (pt,4H), 3.30 (pt, 4H), 2.61 (s, 3H); ¹³CNMR (CDCl₃) δ 143.7, 138.8, 138.0,136.6, 133.9, 129.2, 126.1, 124.3, 123.5, 111.5, 110.0, 107.3, 48.5,43.8, 14.6; MS (ESI) 356.4 (M+H).

EXAMPLE 105 EXAMPLE 106 Intermediate

[0316] N-(t-Butyl-dimethylsilyl-4-(4-boc-homopiperazinyl)-indole

[0317] The title compound was prepared according as Example 4.

[0318]¹H NMR (D₂O) δ 9.37 (bs, 2H) NH; 7.95 (m, 2H); 7.73-7.56 (m, 4H);7.44 (d, J=8.2, 1H); 7.18 (t, J=8.2, 1H); 6.84 (m, 1H); 6.65 (d, J=7.9,1H); 3.65 (m, 2H); 3.46 (m, 2H); 3.31 (m, 2H); 3.19 (m, 2H); 2.13 (m,2H). ¹³C NMR (D₂O): 145.7, 137.5, 136.3, 135.2, 130.4, 127.3, 126.2,125.1, 121.3, 109.3, 105.4, 100.0, 50.8, 48.7, 46.6, 45.1, 25.6. MS(ESI) 356 (M+H).

EXAMPLE 107 Intermediate

[0319]1-Phenylsulfonyl-N-(t-butyl-dimethylsilyl-4-(4-boc-homopiperazinyl)-indole

[0320]¹H NMR (CDCl₃) δ 7.86 (m, 2H); 7.54-7.38 (m, 6H); 7.4 (t, J=8.2,1H); 6.65-6.62 (m, 1H); 3.63-3.41 (m, 8H); 1.97 (m, 2H); 1.43 (s, 9H);MS (ESI) 456 (M+H).

EXAMPLE 108

[0321] 1-Phenylsulfonyl-4-(homopiperazinyl)-indole Hydrochloride

[0322]¹H NMR (CDCl₃): 7.24 (m, 2H); 7.09-7.07 (m, 6H); 7.01 (t, J=8.1,1H); 6.53 (m, 1H); 3.69-3.28 (m, 8H); 2.06 (m, 2H); 1.42 (s, 9H); 0.91(s, 9H); 0.56 (s, 6H). MS (ESI) 430 (M+H).

EXAMPLE 108

[0323] Pharmacological Tests

[0324] The ability of a compound of the invention to bind the 5HT₆receptor can be determined using in vivo and in vitro assays known inthe art. The biological activity of compounds prepared in the Exampleswas tested using different tests.

[0325] 5-HT₆ Intrinsic Activity Assay

[0326] Antagonists at the 5HT₆ receptor were characterized by measuringinhibition of 5-HT induced increase in cAMP in HEK 293 cells expressingthe human 5-HT₆ receptor (see Boess et al. (1997) Neuropharmacology 36:713-720). Briefly, HEK293/5-HT₆ cells were seeded in polylysine coated96-well plates at a density of 25 000/well and grown in DMEM (Dubecco'sModified Eagle Medium) (without phenol-red) containing 5% dialyzedFoetal Bovine Serum for 48 hours at 37° C. in a 5% CO₂ incubator. Themedium was then aspirated and replaced by 0.1 ml assay medium (HanksBalance Salt Solution containing 20 mM HEPES, 1.5 mMisobutylmethylxanthine and 1 mg/ml bovine serum albumin). After additionof test substances, 50 μl dissolved in assay medium, the cells wereincubated for 10 min at 37° C. in a 5% CO₂ incubator. The medium wasagain aspirated and the cAMP content was determined using a radioactivecAMP kit (Amersham Pharmacia Biotech, BIOTRAK RPA559). The potency ofantagonists was quantified by determining the concentration that caused50% inhibition of 5-HT (at [5-HT]=8 times EC₅₀) evoked increase in cAMP,using the formula Ki=IC₅₀/(1+[SHT]/EC₅₀). Typically, the 5-HT₆ receptoraffinity values (Ki) were in the range of from 0.1 nM to 2 AM.

[0327] Method for in vivo Assay of Reduction of Food Intake Animals

[0328] Obese (ob/ob) mouse is selected as the primary animal model forscreening as this mutant mouse consumes high amounts of food resultingin a high signal to noise ratio. To further substantiate and compareefficacy data, the effect of the compounds on food consumption is alsostudied in wild type (C57BL/6J) mice. The amount of food consumed during15 hours of infusion of compounds is recorded.

[0329] Male mice (obese C57BL/6JBom-Lepob and lean wild-typeC57BI/6JBom; Bomholtsgaard, Denmark) 8-9 weeks with an average bodyweight of 50 g (obese) and 25 g (lean) are used in all the studies. Theanimals are housed singly in cages at 23+1° C., 40-60% humidity and havefree access to water and standard laboratory chow. The 12/12-hlight/dark cycle is set to lights off at 5 p.m. The animals areconditioned for at least one week before start of study.

[0330] Compounds

[0331] The test compounds are dissolved in solvents suitable for eachspecific compound such as cyclodextrin, cyclodextrin/methane sulfonicacid, polyethylene glycol/methane sulfonic acid, saline. Fresh solutionsare made for each study. Doses of 30, 50 and 100 mg kg⁻¹day⁻¹ are used.The purity of the test compounds is of analytical grade.

[0332] Minipump Implantation

[0333] The animals are weighed at the start of the study and randomizedbased on body weight. Alzet osmotic minipumps (Model 2001D; infusionrate 8 ul/h) are used and loaded essentially as recommended by the Alzettechnical information manual (Alza Scientific Products, 1997; Teeuwesand Yam, 1976). Continuous subcutaneous infusion with 24 hours durationis used. The minipumps are either filled with different concentrationsof test compounds dissolved in vehicle or with only vehicle solution andmaintained in vehicle pre-warmed to 37° C. (approx. 1 h). The minipumpsare implanted subcutaneously in the neck/back region under short actinganesthesia (metofane/enflurane). This surgical procedure lastsapproximately 5 min. It takes about 3 h to reach steady state deliveryof the compound.

[0334] Food Intake Measurements

[0335] The weight of the food pellets are measured at 5 p.m. and at 8p.m. for two days before (baseline) and one day after the implantationof the osmotic minipumps. The weigh-in is performed with a computerassisted Mettler Toledo PR 5002 balance. Occasional spillage iscorrected for. At the end of the study the animals are killed by neckdislocation and trunk blood sampled for later analysis of plasma drugconcentrations.

[0336] Determination of Plasma Concentration

[0337] The plasma sample proteins are precipitated with methanol,centrifuged and the supernatant is transferred to HPLC vials andinjected into the liquid chromatography/mass spectrometric system. Themass spectrometer is set for electrospray positive ion mode and MultipleReaction Monitoring is used.

[0338] A linear regression analysis of the standards forced through theorigin is used to calculate the concentrations of the unknown samples.

[0339] Statistical Evaluation

[0340] Food consumption for 15 hours is measured for the threeconsecutive days and the percentage of basal level values is derived foreach animal from the day before and after treatment. The values areexpressed as mean ±SD and ±SEM from eight animals per dose group.Statistical evaluation is performed by Kruskal-Wallis one-way ANOVAusing the per cent basal values. If statistical significance is reachedat the level of p<0.05, Mann-Whitney U-test for statistical comparisonbetween control and treatment groups is performed.

What is claimed is:
 1. A compound of formula (I):

wherein Ar is (1) phenyl, (2) naphthyl, (3) a 5- to 10-memberedmonocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatomsselected from the group consisting of oxygen, sulfur, or nitrogen, or(4) —R⁹-phenyl; wherein the phenyl, naphthyl, or heterocyclic ring isoptionally substituted with halogen, C₁₋₆ alkyl, CF₃, hydroxyl, C₁₋₆alkoxyl, OCF₃, COCF₃, CN, NO₂, phenyloxy, phenyl, C₁₋₆ alkylsulfonyl,C₂₋₆ alkenyl, —NR⁷R⁸, C₁₋₆ alkylcarboxyl, formyl, —C₁₆alkyl-NH—CO-phenyl, —C₁₋₆ alkyl-CO—NH-phenyl, —NH—CO—C₁₋₆ alkyl,—CO—NR⁷R⁸, or SR⁷; wherein each of R⁷ and R8 is independently H or C₁₋₆alkyl; and R⁹ is C₁₋₆ alkyl or C₂₋₆ alkenyl, either of which isoptionally substituted with phenyl or phenyloxy; R² is H, phenyl, I, orC₁₋₆ alkyl; R³ is H or 3-(1-azabicyclo[2.2.2]oct-2-en)yl; R⁴ is H or isselected from the group consisting of:

wherein R⁶ is H, C₁₋₆ alkyl, or benzyl; and R⁵ is H, hydroxy, C₁₋₃alkoxy, F, NO₂, CF₃, OCF₃, or is selected from the group consisting of:

or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof,with the proviso that when R² is alkyl, R⁴ is not H.
 2. The compoundaccording to claim 1, wherein Ar is (1) phenyl that is unsubstituted oroptionally mono- or poly-substituted with halogen, C₁₋₆ alkyl, CF₃,hydroxyl, C₁₋₆ alkoxyl, OCF₃, CN, NO₂ phenyloxyl, phenyl, alkylsulfonyl,C₁₋₆ alkenyl, —NH₂, —NHR⁷, —NR⁷R⁸, C₁₋₆ alkylcarboxyl, formyl,NH—CO—C₁₋₆ alkyl, —CO—NR⁷R⁸, or SR⁷ wherein each of R⁷ and R⁸ isindependently H or C₁₋₆ alkyl; (2) 1-naphthyl or 2-naphthyl that isunsubstituted or optionally mono- or poly-substituted with halogen, C₁₋₆alkyl, CF₃, hydroxyl, C₁₋₆ alkoxyl, OCF₃, CN, NO₂ phenyloxyl, phenyl,alkylsulfonyl, C₁₋₆ alkenyl, —NH₂, —NHR⁷, —NR⁷R⁸, C₁₆ alkylcarboxyl,formyl, —NH—CO—C₁₋₆ alkyl, —CO—NR⁷R⁸, or SR⁷ wherein each of R⁷ and R⁸is independently H or C₁₋₆ alkyl; (3) cynnamoyl; (4) benzyl; (5)1,1-diphenylethyl; (6) a monocyclic or bicyclic heterocyclic ringselected from the group consisting of furyl, pyrrolyl, triazolyl,diazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl,thiadiazolyl, pyrimidyl, pyrazinyl, thienyl, imidazolyl, pyrazolyl,indolyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl, andbenzoxadiazolyl, said heterocyclic ring being optionally mono- ordi-substituted substituted with halogen or C₁₋₆ alkyl; R⁴ is H or isselected from the group consisting of:

wherein R⁶ is H, C₁₋₆ alkyl, or benzyl; and R⁵ is H, hydroxy, C₁₋₃alkoxy, F, NO₂, CF₃, OCF₃ or is selected from the group consisting of:


3. A compound according to claim 1, wherein Ar is (1) phenyl, (2)1-naphthyl or 2-naphthyl, (3) a 5- to 10-membered monocyclic or bicyclicheterocyclic ring having 1 to 4 heteroatoms selected from the groupconsisting of oxygen, sulfur, or nitrogen, or (4) -R⁹-phenyl; whereinthe phenyl, naphthyl, or heterocyclic ring is optionally substitutedwith F, Cl, Br, C₁₋₆ alkyl, CF₃, hydroxyl, C₁₋₆ alkoxyl, OCF₃, phenyl,C₂₋₆ alkenyl, —NR⁷R⁸, —NH—CO—C₁₋₆ alkyl, or SR⁷, wherein each of R⁷ andR⁸ is independently H or C₁₋₆ alkyl; and R⁹ is C₁₋₂ alkyl; R² is H,phenyl, I, or C₁₋₆ alkyl; R⁴ is selected from the group consisting of

R⁵ is C₁₋₃ alkoxy or a heterocyclic ring selected from the groupconsisting of:


4. A compound according to claim 1, wherein Ar is phenyl, optionallysubstituted with F, Cl, Br, methyl, CF₃, C₁₋₄ alkoxyl, OCF₃, CN, NO₂,phenyloxy, phenyl, methylsulfonyl, or —NR⁷R⁸, where each of R⁷ and R⁸ isindependently H or methyl.
 5. A compound according to claim 1, whereinAr is 1-naphthyl or 2-naphthyl, each of which is optionally substitutedwith F, Cl, Br, methyl, CF₃, C₁₋₄ alkoxyl, OCF₃, CN, NO₂, phenyloxy,phenyl, methylsulfonyl, or —NR⁷R⁸, where each of R⁷ and R⁸ isindependently H or methyl.
 6. A compound according to claim 1, whereinAr is a heterocyclic ring selected from the group consisting of fuiryl,pyrrolyl, triazolyl, diazolyl, oxazolyl, thiazolyl, oxadiazolyl,isothiazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrimidyl, pyrazinyl,thienyl, imidazolyl, pyrazolyl, indolyl, quinolinyl, isoquinolinyl,benzofuryl, benzothienyl, and benzoxadiazolyl, each of which isoptionally substitiuted with halogen, C₁₋₆ alkyl, CF₃, hydroxyl, C₁₋₆alkoxyl, OCF₃, CN, NO₂, phenyloxy, phenyl, C₁₋₆ alkylsulfonyl, C₂₋₆alkenyl, —NR⁷R⁸, C₁₋₆ alkylcarboxyl, formyl, —NH—CO—C₁₋₆ alkyl,—CO—NR⁷R⁸, or SR⁷; wherein each of R⁷ and R⁸ is independently H or C₁₋₆alkyl.
 7. A compound according to claim 1, wherein Ar is a heterocyclicring selected from the group consisting of pyridinyl, thienyl,imidazolyl, pyrazolyl, benzothienyl, and benzoxadiazolyl, each of whichis optionally substituted with halogen or C₁₋₆ alkyl.
 8. A compoundaccording to claim 1, wherein Ar is 2-pyridyl, 3-pyridyl, or 4-pyridyl.9. A compound according to claim 1, wherein Ar is a 5- to 7-memberedaromatic, partially saturated, or completely saturated heterocyclic ringhaving 1 to 4 heteroatoms selected from the group consisting of O, S, orNR¹⁰, where R¹⁰ is H, C₁₋₆ alkyl, —CO—CF₃, or absent.
 10. A compoundaccording to claim 1, wherein Ar is —R⁹-phenyl, wherein R⁹ is C₁₋₃ alkylor C₂₋₃ alkenyl, either of which is optionally substituted with phenylor phenyloxy, each phenyl being optionally substituted with F, Cl, Br,methyl, CF₃, C₁₋₄ alkoxyl, OCF₃, CN, NO₂, phenyloxy, phenyl,methylsulfonyl, or —NR⁷R⁸; and each of R⁷ and R⁸ being independently Hor C₁₋₆ alkyl.
 11. A compound according to claim 1, wherein each of R²and R³ is H.
 12. A compound according to claim 1, wherein each of R⁴ andR⁵ is independently H or a heterocyclic ring selected from the groupconsisting of:

wherein R⁶ is H, C₁₋₃ alkyl, or benzyl.
 13. A compound according toclaim 1, wherein Ar is phenyl, optionally substituted with F, Cl, Br,methyl, CF₃, C₁₋₄ alkoxyl, OCF₃, CN, NO₂, phenyloxy, phenyl,methylsulfonyl, or —NR⁷R⁸ where each of R⁷ and R⁸ is independently H ormethyl; each of R² and R³ is H; and each of R⁴ and R⁵ is independently Hor a heterocyclic ring selected from the group consisting of:

wherein R⁶ is H, C₁₋₃ alkyl, or benzyl.
 14. A compound according toclaim 1, wherein Ar is 1-naphthyl or 2-naphthyl, each of which isoptionally substituted with F, Cl, Br, methyl, CF₃, C₁₋₄ alkoxyl, OCF₃,CN, NO₂, phenyloxy, phenyl, methylsulfonyl, or —NR⁷R⁸, where each of R⁷and R⁸ is independently H or methyl; each of R² and R³ is H; and each ofR⁴ and R⁵ is independently H or a heterocyclic ring selected from thegroup consisting of:

wherein R⁶ is H, C₁₋₃ alkyl, or benzyl.
 15. A compound according toclaim 1, wherein Ar is a heterocyclic ring selected from the groupconsisting of pyridinyl, thienyl, imidazolyl, pyrazolyl, benzothienyl,and benzoxadiazolyl, each being optionally substituted with halogen orC₁₋₆ alkyl; each of R² and R³ is H; and each of R⁴ and R⁵ isindependently H or a heterocyclic ring selected from the groupconsisting of:

wherein R⁶ is H, C₁₋₃ alkyl, or benzyl.
 16. A compound according toclaim 1, wherein Ar is 2-pyridyl, 3-pyridyl, or 4-pyridyl; each of R²and R³ is H; and each of R⁴ and R⁵ is independently H or a heterocyclicring selected from the group consisting of:

wherein R⁶ is H, C₁₋₃ alkyl, or benzyl.
 17. A compound according toclaim 1, wherein Ar is —R⁹-phenyl; each of R² and R³ is H; and each ofR⁴ and R⁵ is independently H or a heterocyclic ring selected from thegroup consisting of:

wherein R⁶ is H, C₁₋₃ alkyl, or benzyl; R⁹ is C₁₋₃ alkyl or C₂₋₃alkenyl, either of which is optionally substituted with phenyl orphenyloxy; each phenyl being optionally substituted with F, Cl, Br,methyl, CF₃, C,₄ alkoxyl, OCF₃, CN, NO₂, phenyloxy, phenyl,methylsulfonyl, or —NR⁷R⁸; and each of R⁷ and R⁸ being independently Hor C₁₋₆ alkyl.
 18. A compound selected from the group consisting of:1-phenylsulfonyl-4-piperazinylindole hydrochloride,1-[(2,5-dimethoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride, 1-(mesitylsulfonyl)-4-(1-piperazinyl)-1H-indolehydrochloride, 1-(1-naphthylsulfonyl)-4-(1-piperazinyl)-1H-indolehydrochloride,N,N-dimethyl-5-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}-1-naphthalenaminehydrochloride, 1-[(4-propoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride,1-[(2,5-dichloro-3-thienyl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride, 1-[(4-methoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride,1-[(2,4-difluorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride,1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(1-piperazinyl)-1H-indolehydrochloride,1-[(3,4-dimethoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride,5-methyl-2-methoxyl-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenylether hydrochloride,1-[(2,5-dichlorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride,1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride,1-[(3-chloro-2-methylphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride,2-chloro-5-(4-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenoxy)benzonitrilehydrochloride,4-bromo-2-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenyl methyl etherhydrochloride, 4-(1-piperazinyl)-1-(3-pyridinylsulfonyl)-1H-indolehydrochloride,7-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolinehydrochloride, methyl2-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenyl sulfonehydrochloride, 1-[(4-fluorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride,1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride,4-(4-methyl-1-piperazinyl)-1-(4-methylbenzenesulfonyl)-1H-indolehydrochloride hydrochloride,4-piperazino-N-(4-trifluoromethyl)phenylsulfonyl)indole hydrochloride,4-(3-methylpiperazine)-(N-(4-trifluoromethyl)phenylsulfonyl)indoledihydrochloride,4-(4-methyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indolehydrochloride, 4-(4-ethyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole hydrochloride,4-(1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole hydrochloride,4-(5-aza-indolizidinyl)-1-(2-methylbenzenesulfonyl)-1H-indolehydrochloride,4-(4-methyl-1-homopiperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indolehydrochloride,4-(3-methyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indolehydrochloride,4-(cis-3,5-dimethyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indolehydrochloride,4-(4-isopropyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indolehydrochloride,4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptyl)-1-(2-methylbenzenesulfonyl)-1H-indolehydrochloride,4-(4-methyl-1-homopiperazinyl)-1-(benzenesulfonyl)-1H-indolehydrochloride, 4-(cis3,5-dimethyl-1-piperazinyl)-1-(benzenesulfonyl)-1H-indole hydrochloride,4-(4-ethyl-1-piperazinyl)-1-(benzenesulfonyl)-1H-indole hydrochloride,4-piperazinyl-1-(4-nitro-benzenesulfonyl)-1H-indole hydrochloride,4-piperazinyl-1-(4-bromo-benzenesulfonyl)-1H-indole hydrochloride,4-piperazinyl-1-(4-chloro-benzenesulfonyl)-1H-indole hydrochloride,4-piperazinyl-1-(E 2-phenyl-ethensulfonyl)-1H-indole hydrochloride,4-piperazinyl-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indolehydrochloride, 4-piperazinyl-1-(4-cyanobenzenesulfonyl)-1H-indolehydrochloride, 4-piperazinyl-1-(4-chloro-7-chloro-2,1,3-benzoxadiazolesulfonyl)-1H-indole hydrochloride,4-piperazinyl-1-(3-cyanobenzenesulfonyl)-1H-indole hydrochloride,4-piperazinyl-1-(4-phenoxybenzenesulfonyl)-1H-indole hydrochloride,4-piperazinyl-1-(4-chlorophenylmethanesulfonyl)-1H-indole hydrochloride,4-piperazinyl-1-(4-methylphenylmethanesulfonyl)-1H-indole hydrochloride,4-piperazinyl-1-(1,1-diphenylethanesulfonyl)-H-indole hydrochloride,4-piperazinyl-1-(4-trifluoromethoxybenzenesulfonyl)-1H-indolehydrochloride,4-piperazinyl-1-(5-[(benzoylamino)methyl]thiophene-2-sulfonyl)-1H-indolehydrochloride,1-[(N-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1-piperazinyl)-1H-indolehydrochloride, N-benzenesulfonyl-5-(4-methylpiperazin-1-yl)-indole,N-(4-methylbenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole,N-benzenesulfonyl-5-(4-isopropylpiperazin-1-yl)-indole,N-(4-methylbenzenesulfonyl)-5-(4-isopropylpiperazin-1-yl)-indole,N-(3,4-dimethoxybenzenesulfonyl)-5-(4-propylpiperazin-1-yl)-indole,hydrochloride,N-(3-fluorobenzenesulfonyl)-5-(4-propylpiperazin-1-yl)-indole,hydrochloride,N-(4-propylbenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole,hydrochloride,N-(1-naphtalenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole,hydrochloride,N-(biphenyl-4-sulfonyl)-5-(4-methylpiperazin-1-yl)-indole,hydrochloride,N-(4-methoxybenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole,hydrochloride,N-(3,4-dimethoxybenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole,hydrochloride,N-(2,4-difluorobenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole,hydrochloride,N-(4-methoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride,N-(2,4-difluorobenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride,N-(4-butoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride,N-(3,4-dimethoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride,N-(biphenyl-4-sulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride,N-(napthalene-2-sulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride,N-(4-propylbenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride,N-(3-fluorobenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole,hydrochloride, N-(4-methoxybenzenesulfonyl)-5-(piperazin-1-yl)-indole,hydrochloride,N-(2,4-difluorobenzenesulfonyl)-5-(piperazin-1-yl)-indole,hydrochloride, N-(4-butoxybenzenesulfonyl)-5-(piperazin-1-yl)-indole,hydrochloride,N-(3,4-dimethoxybenzenesulfonyl)-5-(piperazin-1-yl)-indole,dihydrochloride, N-(biphenyl-4-sulfonyl)-5-(piperazin-1-yl)-indole,dihydrochloride, N-(napthalene-2-sulfonyl)-5-(piperazin-1-yl)-indole,dihydrochloride, N-(4-propylbenzenesulfonyl)-5-(iperazin-1-yl-indole,dihydrochloride, N-(3-fluorobenzenesulfonyl)-5-(piperazin-1-yl)-indole,dihydrochloride, N-benzenesulfonyl-5-(piperazin-1-yl)-indole,dihydrochloride,3-(1-azabicyclo[2.2.2]oct-2-en-3-yl)-1-[(4-fluorophenyl)sulfonyl]-1H-indole,2-iodo-1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indole hydrochloride,2-phenyl-1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indole hydrochloride,4-piperazinyl-2-methyl-1-benzosulfonylindole trifluoroacetate, and1-phenylsulfonyl-4-(homopiperazinyl)-indole hydrochloride.
 19. Acompound according to claim 1, said compound being1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indole.
 20. A compound accordingto claim 1, said compound being1-[(2,5-dimethoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole.
 21. Acompound according to claim 1, said compound being4-(1-piperazinyl)-1-(3-pyridinylsulfonyl)-1H-indole hydrochloride.
 22. Apharmaceutical composition comprising a compound of claim and apharmaceutically acceptable carrier.
 23. A pharmaceutical compositioncomprising a compound of claim 18 and a pharmaceutically acceptablecarrier.
 24. A method of treatment or prophylaxis of a disease mediatedby the serotonin related 5-HT₆ receptor comprising administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim
 1. 25. A method of treatment or prophylaxis of adisease mediated by the serotonin related 5-HT₆ receptor comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim
 18. 26. The method according toclaim 24, wherein the disease is obesity.
 27. The method according toclaim 24, wherein the disease is a CNS disorder.